HER3 in cancer: from the bench to the bedside
Journal of Experimental & Clinical Cancer Research volume 41, Article number: 310 (2022)
The HER3 protein, that belongs to the ErbB/HER receptor tyrosine kinase (RTK) family, is expressed in several types of tumors. That fact, together with the role of HER3 in promoting cell proliferation, implicate that targeting HER3 may have therapeutic relevance. Furthermore, expression and activation of HER3 has been linked to resistance to drugs that target other HER receptors such as agents that act on EGFR or HER2. In addition, HER3 has been associated to resistance to some chemotherapeutic drugs. Because of those circumstances, efforts to develop and test agents targeting HER3 have been carried out. Two types of agents targeting HER3 have been developed. The most abundant are antibodies or engineered antibody derivatives that specifically recognize the extracellular region of HER3. In addition, the use of aptamers specifically interacting with HER3, vaccines or HER3-targeting siRNAs have also been developed. Here we discuss the state of the art of the preclinical and clinical development of drugs aimed at targeting HER3 with therapeutic purposes.
The ErbB/HER receptor tyrosine kinases (RTK) play critical roles in animal development, and their altered function may contribute to the pathophysiological development of certain types of tumors [1, 2]. In mammals, four ErbB/HER receptors have been described: the epidermal growth factor receptor (EGFR/HER1), HER2/ErbB2/neu, HER3/ErbB3, and HER4/ErbB4 . These receptors are physiologically expressed in epithelial, mesenchymal, cardiac, and neuronal tissues.
Overexpression of HER2 in a subgroup of breast tumors , together with preclinical evidence of an oncogenic role of this transmembrane protein , encouraged the development of agents targeting such receptor. These efforts led to the arrival to the clinic of agents, such as the humanized monoclonal antibody trastuzumab, that by targeting HER2 offered clinical benefit . The clinical success of this strategy led later to the development of agents that targeted the cognate receptor EGFR . The clinical development of agents targeting other ErbB receptors is on the rise due to their suspected role in tumorigenesis or therapy resistance. Thus, expression or overexpression of HER3 has been reported in many cancers, such as breast, ovarian, lung, colorectal, melanoma, head and neck, cervical and prostate cancers [8,9,10,11,12]. Moreover, several studies have pointed to HER3 as a major determinant in resistance to certain therapies, some of them targeting other ErbB receptors . The expression of HER3 in tumors opens the possibility of its targeting with therapeutic purposes. In this review we will discuss the biological bases behind the design of anti-HER3 therapies as well as the clinical status of agents that target this receptor.
HER3: structure, activation, and physiological role
HER3, identified by Kraus et al. , is encoded by the ERBB3 gene and maps to the human chromosome 12q13. HER3 is widely expressed in human adult tissues, including cells of the gastrointestinal, urinary, respiratory, reproductive tracts, skin, endocrine and nervous systems . HER3 consists of a large extracellular domain (ECD), a single hydrophobic transmembrane segment, and an intracellular domain that includes a juxtamembrane region, a tyrosine kinase segment, and a tyrosine-rich carboxyterminal tail (Fig. 1) [16, 17]. The extracellular domain consists of four subdomains, referred to as subdomains I-IV .
Physiological activation of HER3 can be triggered by its interaction with the neuregulins (NRGs), a group of polypeptides that belong to the EGF family of ligands [18, 19]. In the absence of ligand, a direct intramolecular interaction between subdomains II and IV keeps HER3 in an inactive (closed or tethered) conformation . Ligand binding to subdomains I and III provokes a structural change of the extracellular region of the receptor, which acquires an open conformation . Such conformational change results in exposure of the dimerization arm, located in subdomain II. The dimerization arm then allows intermolecular interaction with another ErbB RTK monomer to form dimeric complexes (Fig. 1). Ligand binding also results in changes in the intracellular disposition of the ErbB receptors. Thus, the two kinase domains interact in an asymmetric “head to tail” conformation in which one kinase allosterically activates the other [22, 23].
A debated aspect of HER3 relates to its kinase activity. Initially, it was reported that HER3 lacked kinase activity due to the absence of critical residues necessary for that activity. Later, several reports indicated that HER3 had in fact some tyrosine kinase activity . Although HER3 homodimers have been reported [25,26,27,28], HER3 preferentially dimerizes with other ErbB family members, especially HER2. Indeed, ligand-independent HER2-HER3 heterodimers have also been reported in HER2-amplified (HER2 +) cells . However, such interactions are expected to be weaker and shorter lasting, if compared to ligand-induced dimerization. In fact, studies on the interaction of HER3 and HER2 in breast cancer cells showed that both receptors could only form stable dimers when the HER3 ligand NRG was present . That circumstance opens the relevant question as to how HER3 is constitutively tyrosine phosphorylated in HER2 overexpressing cells. Perhaps, that could be explained by a short but frequent kiss-and-run interaction between HER2 and HER3.
HER3 expression in tumors and clinical outcomes
HER3 expression or overexpression has been described in multiple types of tumors, including breast , ovarian [32, 33], lung , colon , pancreatic , melanoma , gastric [9, 36], head and neck  and prostate cancers . Analysis of the TCGA dataset using the cBioportal online tool (accessed June 2022) shows that melanomas represent the tumor type with the highest HER3 expression at the mRNA level, followed by cholangiocarcinomas and invasive breast tumors. Melanoma metastases commonly have greater HER3 expression than primary tumors . HER3 overexpression has also been found in pilocytic astrocytoma, a childhood glioma,  and in rhabdomyosarcoma, a pediatric sarcoma .
Ocaña et al. performed a meta-analysis evaluating the association of HER3 expression and patient outcome in solid tumors using published information . It was observed that HER3 was overexpressed in 42% of the tumors and in some of them, including melanoma, cervical, or ovarian cancers, HER3 was highly expressed in more than 50% of the cases. In addition, HER3 was associated with worse overall survival in several tumors, especially in HER2-overexpressing cancers. HER3 is overexpressed in human papillomavirus positive (HPV +) models of human tumors and is a prognostic factor for poor outcome in pharyngeal cancer . HER3 is also overexpressed in some prostate cancers [41, 42] and is associated with poor prognosis . Additional studies reported that HER3 overexpression is related with poor prognosis in non-small cell lung cancers (NSCLC) and decreased survival in early-stages [11, 43, 44].
Overexpression of HER3 is often associated with overexpression of HER2 and/or EGFR, playing an important role as co-receptor in HER2 + breast cancer and in a subset of EGFR-positive lung tumors [45,46,47,48]. Furthermore, breast cancers often show co-expression and positive correlation between HER2 and HER3 [49, 50]. This co-expression leads to decreased patient survival . In addition, HER3 is significantly expressed in estrogen receptor positive (ER +) or luminal breast cancer, being essential for cell survival in the luminal but not basal breast epithelium [52, 53].
Finally, little data is reported regarding the presence of oncogenic mutations of ERBB3. These mutations have been mostly reported in gastric and colon adenocarcinomas, and less frequently in NSCLC. Mutant ERBB3 oncogenic forms appear to be ligand-independent and require HER2 . Currently, ERBB3 mutations are on study due to potential therapeutic implications [55,56,57,58].
Biological role of HER3 in therapeutic resistance
HER3 has been implicated in resistance to therapies targeting other HER receptors as well as in resistance to chemotherapies.
When a certain ErbB receptor is blocked, other RTKs may compensate the signaling lost by the blocked receptor. For example, when EGFR is targeted with small molecule tyrosine kinase inhibitors (TKIs) and resistance develops, the signaling blockade can be overcome by an increase in HER3 expression  or amplification of another receptor kinase like MET . Resistance to the anti-EGFR antibody cetuximab in lung cancer is also associated with deregulation of EGFR internalization/degradation and may be associated to activation of HER3 . Also, HER3 signaling has been linked to resistance to TKIs targeting the EGFR in head and neck squamous cell carcinoma (HNSCC) . Huang et al. found that the heterotrimeric HER2-HER3/IGF1R leads to trastuzumab resistance triggering PI3K/AKT and Src kinase signaling . Upregulation of HER3 expression or signaling have also been associated with resistance to lapatinib or trastuzumab in HER2 + breast cancer [63,64,65,66,67].
The expression of the HER3 ligands has been reported to facilitate activation of HER3 leading to resistance to agents targeting other HER receptors. Thus, increased expression and activation of HER3 accompanied by expression of NRG have been reported in HER2 + breast cancer cells resistant to the antibody–drug conjugate (ADC) trastuzumab-emtansine (T-DM1) . This increase in the expression/signaling of HER3 has also been associated with resistance to the insulin-like growth factor 1 receptor (IGF1R) inhibitors in hepatocarcinoma . In this line, high expression of NRG has been reported to be a possible mechanism of resistance to cetuximab in colorectal cancer . Interestingly, in a subset of ovarian cancers, autochtonous production of NRG has been discovered to stimulate proliferation via an autocrine loop involving NRG and HER3 .
As mentioned above, besides its role in resistance to targeted therapies, HER3 may also play a role in resistance to chemotherapy. In HER2 + breast cancer, elevated HER3 expression results in resistance to paclitaxel via upregulation of survivin . Moreover, co-expression of HER2 and HER3 in breast cancer cell lines was associated with resistance to a broad-spectrum of chemotherapeutic agents, likely through up-regulation of PI3K/AKT signaling . HER3 signaling and expression may also play a role in the development of chemoresistance in ovarian cancer [74, 75]. In prostate cancer, HER3/PI3K/AKT signaling has been implicated in the development of hormone resistance and progression to docetaxel resistance . HER3 has also been reported to play a significant role in anti-estrogen (fulvestrant, tamoxifen) resistance in ER + breast cancer [77,78,79,80]. In addition, upregulation of HER3 expression has been reported to be related to resistance to RAF and MEK inhibitors in melanoma and thyroid carcinomas [81, 82].
Current anti-HER3 therapies
In the following section we will describe current strategies to target HER3, which are essentially based on the use of antibodies that recognize the extracellular region of HER3. Figure 2 shows a schematic representation of the therapies described below and Fig. 3 the tumors in which have been reported promising clinical activity.
Under clinical development
All clinical trials of monoclonal antibodies (mAbs) in clinical evaluation are summarized in Table 1.
Lumretuzumab (RG7116, RO5479599, GE-huMab-HER3)
Lumretuzumab is a humanized glycoengineered IgG1 directed to subdomain I of the HER3-extracellular domain . The antibody prevents NRG binding and therefore receptor heterodimerization and activation. It also induces HER3 downregulation. In various tumor xenograft models, lumretuzumab alone or in combination with other anti-HER therapies, caused substantial tumor growth inhibition, including some complete remissions. Lumretuzumab binds to human FcγRIIIa on immune effector cells with more affinity than standard non-glycoengineered antibodies, provoking enhanced antibody-mediated cell-dependent cytotoxicity (ADCC). In xenograft models of ER + /HER3 + /HER2-low human breast cancers, a lumretuzumab and pertuzumab combination was potent and induced long-lasting tumor regression . Indeed, an increase in efficacy was observed if fulvestrant was added. A patient with ER + /HER3 + /HER2-low breast cancer had a prolonged clinical response when she was treated with lumretuzumab + pertuzumab + paclitaxel. Recently, it has been reported that two patients benefited from lumretuzumab plus erlotinib treatment in lung cancer .
ISU104 is a fully human anti-HER3 antibody that binds to subdomain III and is in early clinical development [87, 88]. This antibody downregulates HER3, inhibits NRG binding, blocks dimerization with other HER partners and inactivates the downstream signaling from HER3. In vivo, ISU104 showed more than 70% tumor growth inhibition in HNSCC, NSCLC, colon, pancreatic, breast and skin xenograft cancer models [117, 118]. ISU104 has also showed anti-tumor effects in acquired cetuximab-resistant xenografts either alone or in combination with cetuximab . Recently, Hong et al. have reported anti-tumor efficacy of ISU104 in models with high NRG1 expression or harboring genetic alterations such as NRG1-fusion or oncogenic ERBB3 mutations .
CDX-3379 is a human monoclonal antibody (IgG1λ) that binds with very high affinity to a unique epitope in the boundary between domains II and III and locks HER3 in its inactive state [121, 122]. For this reason, this antibody inhibited both ligand dependent and ligand independent HER3 activation. Its Fc region contains 3 amino acid substitutions, that are referred to as YTE, which increase IgG affinity for human FcRn . CDX-3379 has shown its efficacy in NRG-driven tumors, HER2-amplified breast xenograft models and HPV + models [40, 122]. Preclinically, CDX-3379 in combination with cetuximab or BYL719 (a PI3Kα-selective inhibitor) enhanced growth inhibition in HNSCC xenograft models [124, 125]. In clinical trials, CDX-3379 alone or in combination with cetuximab was well tolerated and caused tumor regression in HNSCC [90, 91]. Other clinical trials have confirmed the safety profile of CDX-3379 combined with other HER therapies or vemurafenib [89, 92].
AV-203 is a humanized IgG1 mAb against HER3 that inhibits NRG binding [126,127,128]. AV-203 inhibits both ligand-dependent and ligand-independent HER3 signaling and downregulates HER3. This mAb has been reported to inhibit tumour growth in xenograft models derived from human NSCLC, breast, pancreatic, kidney, head and neck and esophageal cancer models. In a phase I clinical trial AV-203 demonstrated to be safe in metastatic or advanced solid tumors .
GSK2849330 is a chimeric IgG1/IgG3, glycoengineered humanized mAb against subdomain III of HER3 . Due to these modifications, this antibody has high binding affinity to FcγRIIIa and to human complement protein C1q, leading to enhanced ADCC and complement dependent cytotoxicity (CDC). This mAb blocks NRG binding and therefore receptor dimerization and activation. In vivo, GSK2849330 significantly reduces tumour growth in several xenograft models, including models with NRG alterations (fusion or overexpression) [94, 129, 130]. At present, it has been tested in two phase I clinical trials. In NCT01966445, GSK2849330 achieved a durable response in a unique responder with an oncogenic driver CD74-NRG1-rearranged molecular alteration present in a NSCLC tumor [94, 131].
Seribantumab (MM-121, SAR256212)
Seribantumab is a human IgG2 mAb that competes with NRG for binding to HER3. It blocks dimerization and induces HER3 internalization and degradation. MM-121 decreases tumour growth in pancreatic, ovarian (including cisplatin resistant models), prostate, kidney and NRG1-rearranged cancer models [71, 132,133,134,135,136]. In addition, multiple combinations of MM-121 with other anti-HER therapies have been analysed. The combination of MM-121 and trastuzumab inhibited cell growth in HER2 + breast cancer, including trastuzumab resistant models . MM-121 also enhanced the antitumoral activity of chemotherapy in HER2 + breast cancer models resistant to paclitaxel and trastuzumab , and in cisplatin resistant ovarian cancer xenografts . The combination of MM-121 plus erlotinib inhibited the proliferation of pancreatic cancer cells . MM-121 in combination with letrozole resensitized to the latter drug in ER + breast cancer xenografts . Finally, the combination of MM-121 and cetuximab inhibited growth in HNSCC models, including cetuximab resistant models [140, 141] and in engineered mouse models of lung cancers driven by EGFR T790M-L858R . Seribantumab was generally well tolerated and combined safely with several drugs, but did not produce clinical benefit [97,98,99,100, 102, 103].
Patritumab (AMG-888, U3-1287)
Patritumab is a fully human IgG1 mAb that inhibits ligand binding to HER3 and induces receptor internalization and degradation . Patritumab, alone or in combination with an anti-EGFR mAb, reduced NSCLC xenografts growth, including an EGFR TKI-resistant model [142, 143]. In addition, the combination of patritumab plus erlotinib overcame erlotinib resistance induced by NRG in NSCLC models . Patritumab has also shown its potential as single agent and in combination with panitumumab in HNSCC cells and xenografts . The combination of patritumab and radiation treatment enhanced radiation sensitivity in HNSCC and NSCLC . This antibody was also effective against cetuximab resistance mediated by NRG in colorectal cancer . In addition, patritumab in combination with trastuzumab and lapatinib potentiated tumor growth inhibition in HER2 + breast cancer models, including models resistant to trastuzumab . Patritumab has shown capability to potentiate the antitumor activity of vincristine and cyclophosphamide in ES-4 Ewing’s sarcoma xenografts . This mAb is currently being tested in phase I-III clinical trials with encouraging results [106, 107, 109, 150].
Elgemtumab or LJM716 is a fully human IgG1 mAb that binds to an epitope located between domains II and IV of the ECD of HER3, blocking the receptor in a closed conformation and preventing its activation . This antibody inhibits tumor growth in both NRG-expressing and HER2 + cancer models, being more efficient in combination with other anti-HER therapies, such as cetuximab and trastuzumab. The combination of elgemtumab with trastuzumab and lapatinib significantly improved survival of mice with HER2 + breast cancer xenografts. When elgemtumab was given in combination with BYL719/alpelisib (PI3K inhibitor), they synergistically inhibited growth in HER2 + models, including trastuzumab-resistant HER2 + /PIK3CA mutant MDA-MB-453 xenografts . In patients, LJM716 in combination with alpelisib and trastuzumab had antitumor activity but gastrointestinal toxicity . However, this antibody demonstrated clinical activity and safety [110,111,112,113].
REGN1400 is a fully human IgG mAb that inhibits NRG binding and growth of epidermoid carcinoma, breast cancer and HNSCC cell lines and xenografts. REGN1400 in combination with anti-EGFR or anti-HER2 antibodies inhibits tumor growth more potently [154, 155]. REGN1400 in combination with erlotinib or cetuximab has been tested in a phase I trial and was well tolerated .
Sym013 (Pan-HER) is a mixture of 6 mAbs, comprising 3 pairs of mAbs, each targeting EGFR, HER2 and HER3 . This mixture promotes degradation of receptors, induces ADCC and CDC, has effect in the presence of ligands and inhibits activation of the PI3K and ERK pathways. Sym013 was tested in vivo and in vitro against an extensive panel of more than 100 cancer cell lines and in most cases was effective . It is worth mentioning that Sym013 effectively inhibited growth of models resistant to chemotherapy and HER-targeted therapies (e.g., cetuximab, trastuzumab and T-DM1) [156,157,158,159,160]. The combination of Sym013 with single or fractionated radiation in NSCLC and HNSCC xenografts, including cetuximab resistant models, showed a potent antitumor effect and delayed regrowth . Sym013 was under clinical development, but the clinical trial was terminated due to the inadequate safety profile .
In preclinical phase
A3 and A4 are humanized IgG1 mAbs targeting two different HER3 epitopes. These antibodies inhibit NRG binding, phosphorylation of HER3 and promote HER3 downregulation blocking its recycling [162, 163]. A3 and A4 are active in melanoma and pancreatic models, interfering with cell proliferation and migration [164, 165]. In addition, the combination of A3 and A4 with BRAF/MEK inhibitors potently inhibited cell growth and tumor relapse in a xenograft model . Furthermore, combination of A3 with EGFR TKIs synergistically affected cell proliferation and inhibited tumor growth in lung cancer xenografts, including gefitinib-resistant models . In addition, A3 has shown synergistic antitumor effect in combination with an HDAC inhibitor in NSCLC primary tumor cultures .
The anti-HER3 mouse mAb MP-RM-1 and its humanized version EV20 inhibit ligand-dependent and independent activation of HER3, promote its degradation, and inhibit HER2-HER3 dimerization. They have potent anti-tumor effects in breast, pancreatic, ovarian, melanoma and prostate cancer models [168, 169].
SGP1 is a mAb against HER3 and competes with NRG for binding HER3 . This antibody reduces cell growth stimulated by NRG and increases growth inhibition in combination with trastuzumab in breast cancer cells . SGP1, alone or combined with lapatinib, inhibited proliferation in parental and lapatinib-resistant HER2 + breast cancer cells .
The mouse monoclonal 9F7-F11 (non-ligand competitive) and the fully human IgG1 H4B-121 (NRG-competitive) antibodies recognize domain I and III of HER3 respectively, blocked HER2-HER3 dimerization and promote HER3 downregulation [173,174,175]. These antibodies, alone or in combination with anti-HER2 therapies, reduced tumor growth in epidermoid, pancreatic, lung, triple-negative breast cancer (TNBC) and HER2-low cancer cell xenografts.
Okita et al. have recently generated several anti-HER3 rat mAbs (Ab1-Ab7) which induce strong internalization of HER3, inhibition of NRG binding, HER3 phosphorylation and cell growth in several cancer cell lines. Ab4 shows effect in combination with erlotinib in HER2 + breast cancer and colorectal xenografts .
Anti-HER3ECD  antagonizes NRG binding to HER3, increases its internalization, prevents HER2-HER3 dimerization and therefore cell proliferation and migration in invasive breast cancer cell lines . Yosef Yarden’ lab generated mouse mAbs against the ECD of HER3  that accelerate HER3 degradation and inhibit growth in vitro and in tumor-bearing animals, specially NG33 alone or in combination with other anti-HER3 Abs. This antibody is active in erlotinib-resistant models and prevents osimertinib resistance when given in combination with osimertinib and cetuximab in lung cancer models . A mixture of three antibodies (called 3xmAbs) against EGFR, HER2 and HER3 was reported to be effective in lung cancer models resistant to second- and third-generation EGFR inhibitors, expressing mutant forms of EGFR. The triple mAbs combination triggered the degradation of receptors, inhibited cell proliferation, reduced tumor growth and sensitized these resistant cells to cisplatin and other TKIs. Combining 3xmAbs with a low dose osimertinib improved anti-tumor efficacy [181, 182].
1A5 antibody prevents ligand-independent activation of HER3 by binding to the HER3-ECD and 3D4 prevents ligand-dependent activation by blocking NRG binding. Both antibodies have modest antiproliferative activity but act synergistically with trastuzumab in HER2 + gastric models . LMAb3 is an anti-HER3 mAb IgG1 that inhibits growth in an acquired trastuzumab-resistant ovarian cancer model .
Turowec et al. produced IgG 95, a synthetic antibody against open form of HER3 that blocks ligand binding and promotes HER3 ubiquitination, internalization, and downregulation. This antibody has anti-proliferative activity in HER2-amplified breast cancer cells and inhibits tumor growth in pancreatic xenografts .
Three mouse antibodies against HER3, HER3-3, HER3-8 and HER3-10, have been reported to be extremely potent in inhibiting basal proliferation and ligand-induced growth in breast cancer cell lines. HER3-8 and HER3-10 antibodies inhibited HER2-HER3 dimerization. For this reason, HER3-8 was selected to be humanized, and was termed huHER3-8 . HuHER3-8 in combination with a BRAF inhibitor reduced tumor growth and increased durable response in mutant BRAF models of melanoma . In addition, huHER3-8 reduced growth and signaling in wild-type BRAF/NRAS cutaneous melanomas .
IgG 3–43 is a HER3-targeting human antibody that recognizes an epitope between subdomains III and IV of HER3. It competes with NRG for binding to HER3, efficiently inhibits ligand dependent and independent HER3 activation and induces receptor internalization and degradation. IgG 3–43 showed efficacy in gastric, colorectal, lung, breast and HNSCC models [189, 190].
H3Mab‑17 is an IgG2a, kappa mAb generated by immunizing mice with HER3‑overexpressing cells. This antibody has ADCC and CDC properties and decreases growth in colon cancer models .
Hassani et al. generated several mouse mAbs against different HER3 extracellular subdomains with anti-proliferative effect on HER3-expressing cancer cells and some of them with synergistic effects in combination with trastuzumab .
Eliseev et al. developed single-domain antibodies that target the ECD of HER3 obtained originally from immunized llamas and which present anti-proliferative properties .
Limitations of mAbs targeting HER3
Although most of the mAbs have reported moderate clinical activity with toxicity manageable, clinical development for most of them has been discontinued. On the one hand, none of them reported clinically meaningful benefit. On the other hand, combination strategies have been limited either by toxicity , or by lack of efficacy [83, 97,98,99,100, 102, 105]. Bispecific antibodies (bAbs) and ADCs are expected to improve the clinical efficacy of anti-HER3 therapies.
Bispecific antibodies target two different protein epitopes, either on the same protein or in different proteins. The latter may result in increased specificity of the antibody if the two epitopes are located on different proteins expressed or overexpressed in the tumoral tissue. In addition, if the antigen is located on immune cells, the bAb can facilitate the infiltration of immune system cells in the tumor. Table 2 summarizes clinical trials of bAbs against HER3.
Under clinical development
Zenocutuzumab (Zeno, MCLA-128)
Zenocutuzumab is a bAb IgG1 targeting HER2 (domain I) and HER3 (domain III) . Zenocutuzumab has a ‘dock and block’ mechanism: docks to HER2 and blocks ligand binding to HER3 and therefore inhibits oncogenic signaling via HER2-HER3 heterodimers. The mechanism of action of this bAb includes enhanced ADCC activity due to the glycoengineered modification of the IgG1. This bAb has shown efficacy in breast, gastric and pancreatic cancer models, including models resistant to HER2-directed therapies (trastuzumab and T-DM1) and in the presence of high concentrations of NRG. Zenocutuzumab inhibited growth of NRG1 fusion-positive cancer models, also demonstrating efficacy in patients with chemotherapy-resistant NRG1 fusion-positive metastatic cancer . Zenocutuzumab is currently being tested in phase I/II clinical trials, which reported well tolerated safety profile as well as anti-tumor activity [194, 195].
SI-B001 is an IgG-(scFv)2 bAb that targets EGFR and HER3. This bispecific tetravalent antibody is based in the model of an IgG-(scFv)2 structure that consists of a complete IgG with two heavy and two light chains, and two scFv components connected to either C or N terminals of the heavy or light chains . SI-B001 has recently demonstrated its efficacy in colon, HNSCC and esophageal cancer xenograft models, achieving almost complete inhibition of the growth in the last two models . SI-B001 is now being tested in phase I and II clinical trials.
MM-111 is a bAb directed to HER2 and HER3 in which the anti-HER2 arm localizes the bAb in HER2 + tumor cells and the anti-HER3 arm blocks NRG binding [209, 210]. This bAb is synthesized as single polypeptide fusion protein of two human scFv binding arms, targeting HER2 and HER3, linked to modified human serum albumin. In preclinical studies, this bAb decreased growth in HER2 + gastric, breast, ovarian, and lung cancer models and demonstrated an increased antitumor activity combined with trastuzumab or lapatinib in HER2 + breast cancer. In a clinical trial, this bAb reported to be safe also in combination with standard of care HER2-targeting drugs and chemotherapy . However, the phase II clinical trial NCT01774851 in HER2 expressing gastroesophageal cancers was terminated early due to lack of effect of MM-111 plus paclitaxel and trastuzumab . Because of this disappointing result, all further studies investigating MM-111 were revoked.
Istiratumab is a tetravalent bAb holding 4 high-affinity binding sites, two are specific for IGF1R and two for HER3 [211,212,213]. Structurally, istiratumab contains an IgG1 mAb against IGF1R that was engineered to contain two single-chain Fv fragments targeting HER3 fused at the C terminus of the heavy chain. Notably, istiratumab blocks ligand binding (NRG and IGF-1/2), downregulates receptor levels and suppresses downstream signaling. Istiratumab demonstrated its potential inhibition of growth in multiple models including pancreatic, sarcoma, renal, ovarian, melanoma and prostate cancer. This bAb potentiated the anti-tumoral effects of chemotherapy and of the mTOR inhibitor everolimus in models of pancreatic and ovarian cancer [211, 212, 214]. Istiratumab has been evaluated in clinical trials with disappointing results .
Duligotuzumab (MEHD7945A, RG7597)
Duligotuzumab is a humanized bAb IgG1 targeting EGFR and HER3 that blocks ligand binding, inhibits signaling pathways and potentiates ADCC [215, 216]. Duligotuzumab contains two identical Fabs that can bind EGFR or HER3. Duligotuzumab strongly inhibited tumor growth in several preclinical models, including human epidermoid carcinoma, pancreatic, breast, colorectal, HNSCC and lung cancer, especially in combination with chemotherapy. Duligotuzumab demonstrated its efficacy in resistant models to erlotinib and cetuximab derived from HNSCC and NSCLC in monotherapy  or in combination with cisplatin . Its action has also been reported in combination with AKT and PI3K inhibitors in TNBC . In addition, duligotuzumab enhanced the antitumor effect of trastuzumab in HER2 + gastric models . Recently, it has been reported that duligotuzumab increased ionizing radiation response in cervical cancer models . Several clinical trials (phases I/II) are testing duligotuzumab and in general reported limited activity [200,201,202,203,204].
In preclinical phase
Tab6 or TA is a tetravalent and bAb against HER2 and HER3 that consists in the anti-HER2 antibody trastuzumab fused with HER3-specific scFvs derived from a seribantumab biosimilar called Ab6 in its both CH3 domains . Surprisingly, treatment with TAb6 increased the proliferation of HER2 + breast cancer cell lines. However, in the presence of NRG, TAb6 in combination with lapatinib significantly reduced proliferation. In addition, Tab6 restored sensitivity to the PI3K inhibitor GDC-0941 in prostate cancer cells resistant to that inhibitor .
A5/F4 is an oligoclonal mixture of two IgGs based on scFv against domains I (F4) and III (A5) of HER3. A5/F4 inhibits ligand-dependent HER3 signaling, cell proliferation and enhances the activity of HER-targeted agents in vitro and in vivo .
Bispecific molecules called dual variable domain immunoglobulin (DVD-Ig) proteins against EGFR and HER3 have also been developed . These molecules consist of a human IgG1 heavy chain and Igκ light chain constant domains linked with an additional variable domain (VH and VL sequences) at the N terminus of both Fab arms. The HER3-targeting variable domains of the DVD-Igs are derived from seribantumab. In vitro, anti-EGFR/HER3 DVD-Ig proteins were superior inhibiting growth in comparison to parental mAbs combination or a conventional bAb.
Recently, Rau et al. have generated a tetravalent and bAb called scDb hu225 × 3–43-Fc targeting both EGFR and HER3 . This antibody is composed of a bispecific single-chain diabody (scDb) generated by the antigen-binding site of the humanized version of cetuximab (IgG hu225) and the IgG 3–43 (described above) fused to the hinge region of a human Fcγ1 chain (scDb-Fc). Its efficacy blocking proliferation, inhibiting HER phosphorylation, downstream signaling and inducing receptor internalization and degradation has been demonstrated in HNSCC and TNBC models. Indeed, this bAb in combination with trastuzumab is also effective in colorectal cancer models, bypassing NRG-induced resistance to anti-EGFR therapies . The same lab had also generated Dab-Fc 2 × 3 molecule, an innovative bivalent and bispecific molecule (Dab-Fc) that targets HER2 and HER3 with anti-tumoral activity in vitro and in vivo . Dab-Fc comprises the variable domains of trastuzumab (anti-HER2 Ab) and IgG 3–43 (anti-HER3 Ab) assembled into a diabody-like construction stabilized by CH1 and CL domains and fused to a human γ1 Fc region. Recently, IgG 3–43 was used to generate novel and effective scDb‑based trivalent bispecific antibodies directed against HER3 and CD3 that target T‑cells to HER3-expressing cancer cells [229, 230].
1G5D2 is a native bispecific hybridoma mAb with dual specificity for HER3 and HER2 ECDs that strongly inhibited cell proliferation alone or in combination with trastuzumab .
ADCs are a new class of antitumoral agents designed to merge the selectivity of mAbs with the cell killing properties of a cytotoxic drug (payload) attached by a linker to the mAb. That linker may be cleavable or non-cleavable [232, 233].
Under clinical development
U3-1402 (Patritumab deruxtecan, HER3-DXd)
U3-1402 also called patritumab deruxtecan or HER3-DXd is an ADC composed by patritumab covalently conjugated to a drug-linker containing deruxtecan, a topoisomerase I inhibitor . U3-1402 was efficiently internalized, induced HER3 degradation and showed growth inhibition activity in HER3 + breast, gastric and colorectal cancer [234, 235]. U3-1402 is also effective alone or in combination with an EGFR-TKI in EGFR-TKI-resistant NSCLC models, in which EGFR inhibition with osimertinib pretreatment increased U3-1402 efficacy [236,237,238]. Recently, it has been demonstrated that U3-1402 sensitized HER3 + tumors to programmed cell death-1 (PD-1) blockade . Patritumab deruxtecan has demonstrated its clinical efficacy in metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy . U3-1402 is currently under clinical evaluation (Table 3) and has demonstrated antitumor activity and manageable safety profile in breast cancer and EGFR-mutant NSCLC [240,241,242,243,244,245].
In preclinical phase
Gianluca Sala’s group has generated several ADC versions derived from the anti-HER3 antibody EV20: (1) EV20-Sap obtained by coupling the plant toxin saporin, (2) EV20/MMAF, and (3) EV20‑sss‑vc/MMAF, by coupling the cytotoxic drug monomethyl auristatin F with non-cleavable or cleavable linker respectively and (4) EV20/NMS-P945 by coupling EV20 with a DNA minor groove alkylating agent (thienoindole NMS-P528) through a cleavable linker. EV20-Sap has cytotoxic activity in melanoma cells and reduces pulmonary metastases in a murine metastatic model of melanoma . EV20/MMAF demonstrated HER3-dependent cell killing activity in melanoma and in HER2 + breast cancer cell lines and xenografts, including several models of cells resistant to anti-HER2 therapies [247, 248]. EV20/MMAF in combination with PLX4720 in BRAF mutated melanoma, and EV20/MMAF alone or plus vemurafenib resulted in an effective anti-metastatic activity in vivo. EV20‑sss‑vc/MMAF demonstrated its efficacy in HER3 + liver cancer . Recently, EV20/NMS-P945 showed cytotoxic activity on prostate, HNSCC, pancreatic, melanoma, gastric and ovarian cancer .
The anti-HER3 antibody 9F7–F11 had been conjugated with monomethyl auristatin E to generate a novel ADC, MMAE–9F7–F11. This ADC increased arrest in G2/M, which is the most radiosensitive phase of the cell cycle and promoted cell death of HER3 + pancreatic cancer cells . In vivo, MMAE–9F7–F11 in combination with radiation therapy increased the overall survival in a pancreatic cancer mouse model.
Antibody-Derived molecules in preclinical phase
Hu et al. developed tetraspecific antibodies called FL518 and CRTB6 that recognize EGFR, HER2, HER3 and VEGF . CRTB6 was generated by combining the variable regions of cetuximab, trastuzumab, lumretuzumab and bevacizumab into a DVD-Ig–like antibody and FL518 by combining the two bispecific antibodies duligotuzumab (against HER3 and EGFR) and bH1-44 (against HER2 and VEGF). These tetraspecific antibodies were more effective inhibiting signaling and growth than bispecific antibodies in colorectal, breast, pancreatic, lung or gastric cancer models, including anti-HER-resistant cancer cells.
TsAb2v2 and TsAb3v1 are tetraspecific, tetravalent Fc-containing antibodies targeting EGFR, HER3, cMet and IGF1R generated by the combination of N-terminal single-chain Fabs and C-terminal single-chain Fvs in an IgG1 antibody format . The binding arms are derived from imgatuzumab (EGFR), lumretuzumab (HER3), onartuzumab (cMet) and R1507 (IGF1R). These antibodies bind and inhibit all targets at the same time and show higher apoptosis induction and tumor growth inhibition over mAbs or bAbs in pancreatic, breast and lung tumor models.
Trispecific ErbB-cMet-IGF1R antibodies which target EGFR, IGF1R and cMet or EGFR, IGF1R and HER3 have been reported to inhibit receptor activation and cellular growth .
Alternative anti-HER3 antibody-derived formats that provide a similar binding capacity but with improved properties, such as a small size and higher tissue penetration and extravasation have been developed . Among these several novel molecules derived from antibody structures are surrobodies. They are comprised of a diversified immunoglobulin heavy chain and an invariant surrogate light chain that together confer specific high-affinity binding to their targets. Two of these surrobodies, SL-175 and SL-176, reduced growth of several tumor models in vitro and in vivo, and were even more potent in combination with trastuzumab and lapatinib in HER2 + cell lines . Affibodies are three-helix bundle Z-domain based on such domain of staphylococcal protein A that have short plasma half-life time and rapid clearance with low production cost . Recently, several anti-HER3 affibody molecules have been reported with activity in pancreatic and ovarian cancer models [258, 259]. ICG-ZHer3 is a dimeric HER3-specific affibody coupled to a photosensitizer (indocyanine green) that mediated photothermal therapy (transform light into heat energy to kill cancer cells) and had antitumoral properties in HER3 + cancers . Bispecific affibodies against HER3 and HER2 in which two affibodies were linked by an albumin‐binding domain have also been generated . A novel platform developed diabody-Ig and generated active tetravalent bAbs against EGFR and HER3 . The antigen-binding site of these molecules is composed of a diabody in the VH-VL orientation stabilized by fusion to antibody-derived homo- or heterodimerization domains, further fused to an Fc region.
Pan-HER tyrosine kinase inhibitors (pan-TKIs) under clinical development
Due to the reported low activity of the HER3 kinase domain and the requirement of heterodimerization with other HER receptors for its activation, blocking the receptor partners leads to the suppression of HER3 activity. This means that pan-TKIs, which inhibit catalytic activity of HER members, indirectly act as HER3 inhibitors as well [263, 264]. In this review we will not focus on this family of agents.
Other anti-HER3 strategies for cancer therapy
Under clinical development
At present, there are two clinical trials using HER3 vaccines. NCT03832855 is a phase I clinical trial that uses an investigational cancer vaccine called pING-hHER3FL. pING-hHER3FL is a circular piece of DNA that produces the full length human HER3 protein. On the other hand, NCT04348747 is a phase II trial study that uses a dendritic cell vaccine against HER2-HER3, in combination with other drugs that may boost the immune system to recognize and destroy cancer cells.
In preclinical phase
In preclinical studies, a vaccine generated with an adenovirus encoding the full length human HER3 receptor (Ad-HER3 or Ad-HER3-FL) has been evaluated preclinically [265, 266]. Ad-HER3 induced strong T-cell anti-tumor responses and anti-HER3 antibodies that have effectiveness against breast cancer, including models of acquired resistance to HER2-targeted therapies. High efficacy of Ad-HER3-FL in combination with dual PD-1/PD-L1 and CTLA4 blockade treatments has also been reported.
Miller et al. evaluated four HER3 peptides of the HER3-ECD as putative B-cell epitopes to activate the immune system and produce highly specific HER3 antibodies . They reported enhanced anti-tumor effects of these HER3 vaccine antibodies in breast and pancreatic cancer preclinical models. They also reported enhanced response and higher levels of ADCC when the HER3 vaccine antibodies are combined with HER2, HER1 and IGF1R vaccine antibodies.
RB200 is a bispecific ligand trap which binds to HER3 ligand NRG and EGFR ligands . This molecule was generated combining the EGFR and HER3 ligand binding domains with an Fc fragment of human IgG1. RB200 prevents ligand-dependent receptor activation and inhibits proliferation in vitro and in xenograft models.
Several antisense oligonucleotides or microRNAs have been described to be able to downregulate HER3 and inhibit proliferation. EZN-3920 is a HER3 antisense oligonucleotide which has anti-tumor activity alone or combined with TKIs in vitro and in xenograft tumor models, including models of resistance to anti-HER therapies . Several miRNAs such miR-125a, miR-125b, miR-205 and miR-450b-3p suppress HER3 expression by directly targeting 3′ UTR of HER3 mRNA and inhibit proliferation of breast cancer cells [270,271,272].
HER3 siRNAs decrease cell proliferation and sensitize cells to anti-HER therapies [79, 273]. In addition, several authors had developed carriers to direct siRNAs or drugs to cancer cells. For example, HER3 aptamers, artificial single-stranded DNA or RNA oligonucleotides that bind HER3, have been used to target HER3 + tumoral cells. Yu et al. reported the antitumoral action of a three-in-one nucleic acid aptamer-siRNA chimera that targets EGFR-HER2-HER3 in HER2 + breast cancer . Recently, Shu et al. demonstrated the antiproliferative activity of carbon dots/HER3 siRNA, alone or in combination with trastuzumab in HER2 + breast cancer cells . HER3 aptamer-protamine-siRNA (against oncogenes or CDKs) nanoparticles have anticancer effect in HER3 + breast cancer models . In addition, a HER3 aptamer-functionalized liposome encapsulating doxorubicin has been developed to deliver it in HER3 + models . Sorafenib encapsulated in microparticles with anti-HER3 aptamers in the surface diminish the toxicity of sorafenib . An RNA aptamer against HER3-ECD, A30, inhibited NRG signaling and therefore cell growth in breast cancer cells . A30 was also used to deliver a set of cytotoxic siRNAs and inhibit growth in HER3 + breast cancer cells . Recently, a novel RNA aptamer called HBR has been reported to inhibit HER3/NRG interaction .
Xie et al. reported ATP-competitive small molecule inhibitors targeting the pseudokinase of HER3 that can perturb the biological function of HER3 [282, 283]. TX1-85–1 interacts with Cys721 in the ATP-binding pocket of HER3 but has a poor effect in proliferation and HER3-dependent functions in vitro. However, a derivate of TXI-85–1 with a hydrophobic adamantane moiety, TX-121–1, produces covalent modification of HER3, causes partial degradation of HER3, interferes the dimerization of HER3 with c-Met and HER2 and perturbs HER3-dependent signaling and growth.
Sims et al. synthesized a polypeptide called HerPBK10 or HPK which had a minimal receptor binding domain constructed from the structure of NRG1 . It specifically binds to HER3. HPK is inert and it was used to deliver a variety of therapeutic payloads, generating HPK-nanobiologics that mimic the natural ligand-receptor interaction on HER3 but resulting in delivery of a tumor-toxic molecule. For instance, they used doxorubicin to generate H3-D and a sulfonated corrole generating H3-G. These HPK-nanobiologics are effective against trastuzumab-resistant models in a HER3-dependent manner.
Targeting HER3 ligand NRG could be an approach to block this receptor. For example, 7E3 is an antibody directed to NRG1 IgG-like domain that blocks NRG1-dependent growth in pancreatic cancer models . This antibody decreases ligand-induced activation and expression level of HER3 and induces ADCC. There are other anti-NRG antibodies in preclinical stage, such as YW538.24.71 and YW526.90.28 .
In this review it has been summarized several therapies against HER3, most of them in preclinical development. However, nowadays no treatment specifically targeting HER3 has been approved for clinical use. The therapeutic efficacy of an anti-HER3 regimen could be enhance by its combination with other anti-HER therapy, chemo-, immuno-, or radio-therapy. This fact has also been observed with anti-HER2 therapies, because for optimal inhibition of HER2 function in HER2 + breast cancer cells, treatment with at least two anti-HER2 drugs is required. It is hoped that anti-HER3 ADC approach would overcome the shortcomings of mAb-based HER3 therapy, with potent delivery of therapeutics payload to HER3 expressing cancer cells. Indeed, the generation of molecules derived from antibodies with low production cost, short plasma half-life time and rapid clearance have emerged in the field. However, the development of potent prognostic and predictive biomarkers for anti-HER3 targeted therapeutics is also required.
Availability of data and materials
Antibody-mediated cell-dependent cytotoxicity
Complement dependent cytotoxicity
Data and Safety Monitoring Board
Dual variable domain immunoglobulin
Epidermal growth factor receptor
- ER + :
Estrogen receptor positive
Esophageal squamous cell carcinoma
- HER2 + :
Head and neck squamous cell carcinoma
- HPV + :
Human papillomavirus positive
- ID50 and ID90 :
The 50% and 90% inhibitory mass doses
Insulin-like growth factor 1 receptor
Invasive mucinous adenocarcinomas
Non-small cell lung cancers
Pan-tyrosine kinase inhibitors
Programmed cell death-1
Recommended phase 2 dose
Receptor tyrosine kinases
Bispecific single-chain diabody
Tyrosine kinase inhibitors
Triple-negative breast cancer
Maennling AE, Tur MK, Niebert M, Klockenbring T, Zeppernick F, Gattenlohner S, et al. Molecular Targeting Therapy against EGFR Family in Breast Cancer: Progress and Future Potentials. Cancers (Basel). 2019;11(12). https://doi.org/10.3390/cancers11121826.
Esparís-Ogando A, Montero JC, Arribas J, Ocaña A, Pandiella A. Targeting the EGF/HER Ligand-Receptor System in Cancer. Curr Pharm Des. 2016;22(39):5887–98.
Appert-Collin A, Hubert P, Cremel G, Bennasroune A. Role of ErbB Receptors in Cancer Cell Migration and Invasion. Front Pharmacol. 2015;6:283.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–82.
Di Fiore PP, Pierce JH, Kraus MH, Segatto O, King CR, Aaronson SA. erbB-2 is a potent oncogene when overexpressed in NIH/3T3 cells. Science. 1987;237(4811):178–82.
Swain SM, Clark E, Baselga J. Treatment of HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(20):1964–5.
Flynn JF, Wong C, Wu JM. Anti-EGFR Therapy: Mechanism and Advances in Clinical Efficacy in Breast Cancer. J Oncol. 2009;2009:526963.
Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst. 2013;105(4):266–73.
Slesak B, Harlozinska A, Porebska I, Bojarowski T, Lapinska J, Rzeszutko M, et al. Expression of epidermal growth factor receptor family proteins (EGFR, c-erbB-2 and c-erbB-3) in gastric cancer and chronic gastritis. Anticancer Res. 1998;18(4A):2727–32.
Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res. 1995;1(11):1413–20.
Yi ES, Harclerode D, Gondo M, Stephenson M, Brown RW, Younes M, et al. High c-erbB-3 protein expression is associated with shorter survival in advanced non-small cell lung carcinomas. Mod Pathol. 1997;10(2):142–8.
Leung HY, Weston J, Gullick WJ, Williams G. A potential autocrine loop between heregulin-alpha and erbB-3 receptor in human prostatic adenocarcinoma. Br J Urol. 1997;79(2):212–6.
Amin DN, Campbell MR, Moasser MM. The role of HER3, the unpretentious member of the HER family, in cancer biology and cancer therapeutics. Semin Cell Dev Biol. 2010;21(9):944–50.
Kraus MH, Issing W, Miki T, Popescu NC, Aaronson SA. Isolation and characterization of ERBB3, a third member of the ERBB/epidermal growth factor receptor family: evidence for overexpression in a subset of human mammary tumors. Proc Natl Acad Sci U S A. 1989;86(23):9193–7.
Prigent SA, Lemoine NR, Hughes CM, Plowman GD, Selden C, Gullick WJ. Expression of the c-erbB-3 protein in normal human adult and fetal tissues. Oncogene. 1992;7(7):1273–8.
Yarden Y. The EGFR family and its ligands in human cancer signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37(Suppl 4):S3-8.
Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117–34.
Massague J, Pandiella A. Membrane-anchored growth factors. Annu Rev Biochem. 1993;62:515–41.
Montero JC, Rodriguez-Barrueco R, Ocana A, Diaz-Rodriguez E, Esparis-Ogando A, Pandiella A. Neuregulins and cancer. Clin Cancer Res. 2008;14(11):3237–41.
Cho HS, Leahy DJ. Structure of the extracellular region of HER3 reveals an interdomain tether. Science. 2002;297(5585):1330–3.
Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12(3):541–52.
Linggi B, Carpenter G. ErbB receptors: new insights on mechanisms and biology. Trends Cell Biol. 2006;16(12):649–56.
Zhang X, Gureasko J, Shen K, Cole PA, Kuriyan J. An allosteric mechanism for activation of the kinase domain of epidermal growth factor receptor. Cell. 2006;125(6):1137–49.
Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci U S A. 2010;107(17):7692–7.
Berger MB, Mendrola JM, Lemmon MA. ErbB3/HER3 does not homodimerize upon neuregulin binding at the cell surface. FEBS Lett. 2004;569(1–3):332–6.
Pawar AB, Sengupta D. Resolving the conformational dynamics of ErbB growth factor receptor dimers. J Struct Biol. 2019;207(2):225–33.
Steinkamp MP, Low-Nam ST, Yang S, Lidke KA, Lidke DS, Wilson BS. erbB3 is an active tyrosine kinase capable of homo- and heterointeractions. Mol Cell Biol. 2014;34(6):965–77.
Váradi T, Schneider M, Sevcsik E, Kiesenhofer D, Baumgart F, Batta G, et al. Homo- and Heteroassociations Drive Activation of ErbB3. Biophys J. 2019;117(10):1935–47.
Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, et al. Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 2009;15(5):429–40.
Sanchez-Martin M, Pandiella A. Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: therapeutic implications. Int J Cancer. 2012;131(1):244–52.
Bobrow LG, Millis RR, Happerfield LC, Gullick WJ. c-erbB-3 protein expression in ductal carcinoma in situ of the breast. Eur J Cancer. 1997;33(11):1846–50.
Rajkumar T, Stamp GW, Hughes CM, Gullick WJ. c-erbB3 protein expression in ovarian cancer. Clin Mol Pathol. 1996;49(4):M199-202.
Simpson BJ, Weatherill J, Miller EP, Lessells AM, Langdon SP, Miller WR. c-erbB-3 protein expression in ovarian tumours. Br J Cancer. 1995;71(4):758–62.
Ciardiello F, Kim N, Saeki T, Dono R, Persico MG, Plowman GD, et al. Differential expression of epidermal growth factor-related proteins in human colorectal tumors. Proc Natl Acad Sci U S A. 1991;88(17):7792–6.
Reschke M, Mihic-Probst D, van der Horst EH, Knyazev P, Wild PJ, Hutterer M, et al. HER3 is a determinant for poor prognosis in melanoma. Clin Cancer Res. 2008;14(16):5188–97.
Rajkumar T, Gooden CS, Lemoine NR, Gullick WJ, Goden CS. Expression of the c-erbB-3 protein in gastrointestinal tract tumours determined by monoclonal antibody RTJ1. J Pathol. 1993;170(3):271–8.
Zhang J, Saba NF, Chen GZ, Shin DM. Targeting HER (ERBB) signaling in head and neck cancer: An essential update. Mol Aspects Med. 2015;45:74–86.
Addo-Yobo SO, Straessle J, Anwar A, Donson AM, Kleinschmidt-Demasters BK, Foreman NK. Paired overexpression of ErbB3 and Sox10 in pilocytic astrocytoma. J Neuropathol Exp Neurol. 2006;65(8):769–75.
Nordberg J, Mpindi JP, Iljin K, Pulliainen AT, Kallajoki M, Kallioniemi O, et al. Systemic analysis of gene expression profiles identifies ErbB3 as a potential drug target in pediatric alveolar rhabdomyosarcoma. PLoS ONE. 2012;7(12):e50819.
Brand TM, Hartmann S, Bhola NE, Peyser ND, Li H, Zeng Y, et al. Human Papillomavirus Regulates HER3 Expression in Head and Neck Cancer: Implications for Targeted HER3 Therapy in HPV(+) Patients. Clin Cancer Res. 2017;23(12):3072–83.
Soler M, Mancini F, Meca-Cortes O, Sanchez-Cid L, Rubio N, Lopez-Fernandez S, et al. HER3 is required for the maintenance of neuregulin-dependent and -independent attributes of malignant progression in prostate cancer cells. Int J Cancer. 2009;125(11):2565–75.
Koumakpayi IH, Diallo JS, Le Page C, Lessard L, Gleave M, Begin LR, et al. Expression and nuclear localization of ErbB3 in prostate cancer. Clin Cancer Res. 2006;12(9):2730–7.
Muller-Tidow C, Diederichs S, Bulk E, Pohle T, Steffen B, Schwable J, et al. Identification of metastasis-associated receptor tyrosine kinases in non-small cell lung cancer. Cancer Res. 2005;65(5):1778–82.
Fujimoto N, Wislez M, Zhang J, Iwanaga K, Dackor J, Hanna AE, et al. High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor. Cancer Res. 2005;65(24):11478–85.
Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A. 2003;100(15):8933–8.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316(5827):1039–43.
Stern DF. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J Mammary Gland Biol Neoplasia. 2008;13(2):215–23.
Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, et al. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers. Cell Rep. 2022;38(5): 110291.
Bieche I, Onody P, Tozlu S, Driouch K, Vidaud M, Lidereau R. Prognostic value of ERBB family mRNA expression in breast carcinomas. Int J Cancer. 2003;106(5):758–65.
McIntyre E, Blackburn E, Brown PJ, Johnson CG, Gullick WJ. The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer. Breast Cancer Res Treat. 2010;122(1):105–10.
Wiseman SM, Makretsov N, Nielsen TO, Gilks B, Yorida E, Cheang M, et al. Coexpression of the type 1 growth factor receptor family members HER-1, HER-2, and HER-3 has a synergistic negative prognostic effect on breast carcinoma survival. Cancer. 2005;103(9):1770–7.
Morrison MM, Hutchinson K, Williams MM, Stanford JC, Balko JM, Young C, et al. ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest. 2013;123(10):4329–43.
Balko JM, Miller TW, Morrison MM, Hutchinson K, Young C, Rinehart C, et al. The receptor tyrosine kinase ErbB3 maintains the balance between luminal and basal breast epithelium. Proc Natl Acad Sci U S A. 2012;109(1):221–6.
Jaiswal BS, Kljavin NM, Stawiski EW, Chan E, Parikh C, Durinck S, et al. Oncogenic ERBB3 mutations in human cancers. Cancer Cell. 2013;23(5):603–17.
Kiavue N, Cabel L, Melaabi S, Bataillon G, Callens C, Lerebours F, et al. ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics. Oncogene. 2020;39(3):487–502.
Mishra R, Alanazi S, Yuan L, Solomon T, Thaker TM, Jura N, et al. Activating HER3 mutations in breast cancer. Oncotarget. 2018;9(45):27773–88.
Ross JS, Fakih M, Ali SM, Elvin JA, Schrock AB, Suh J, et al. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. Cancer. 2018;124(7):1358–73.
Li M, Liu F, Zhang F, Zhou W, Jiang X, Yang Y, et al. Genomic ERBB2/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut. 2019;68(6):1024–33.
Frolov A, Schuller K, Tzeng CW, Cannon EE, Ku BC, Howard JH, et al. ErbB3 expression and dimerization with EGFR influence pancreatic cancer cell sensitivity to erlotinib. Cancer Biol Ther. 2007;6(4):548–54.
Wheeler DL, Huang S, Kruser TJ, Nechrebecki MM, Armstrong EA, Benavente S, et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene. 2008;27(28):3944–56.
Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P, et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res. 2006;12(13):4103–11.
Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X, et al. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin. Cancer Res. 2010;70(3):1204–14.
Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007;445(7126):437–41.
Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, et al. Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 2007;13(16):4909–19.
Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD, Maihle NJ. Trastuzumab-induced HER reprogramming in “resistant” breast carcinoma cells. Cancer Res. 2009;69(6):2191–4.
Garrett JT, Olivares MG, Rinehart C, Granja-Ingram ND, Sanchez V, Chakrabarty A, et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc Natl Acad Sci U S A. 2011;108(12):5021–6.
Lyu H, Yang XH, Edgerton SM, Thor AD, Wu X, He Z, et al. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells. Oncotarget. 2016;7(3):2921–35.
Phillips GD, Fields CT, Li G, Dowbenko D, Schaefer G, Miller K, et al. Dual targeting of HER2-positive cancer with trastuzumab emtansine and pertuzumab: critical role for neuregulin blockade in antitumor response to combination therapy. Clin Cancer Res. 2014;20(2):456–68.
Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoel MJ, Fartoux L, Venot C, Bladt F, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res. 2009;15(17):5445–56.
Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, et al. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.
Sheng Q, Liu X, Fleming E, Yuan K, Piao H, Chen J, et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell. 2010;17(3):298–310.
Wang S, Huang X, Lee CK, Liu B. Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin. Oncogene. 2010;29(29):4225–36.
Knuefermann C, Lu Y, Liu B, Jin W, Liang K, Wu L, et al. HER2/PI-3K/Akt activation leads to a multidrug resistance in human breast adenocarcinoma cells. Oncogene. 2003;22(21):3205–12.
Bezler M, Hengstler JG, Ullrich A. Inhibition of doxorubicin-induced HER3-PI3K-AKT signalling enhances apoptosis of ovarian cancer cells. Mol Oncol. 2012;6(5):516–29.
Amler L, Makhija S, Januario T, Lin C-Y, Derynck M, Birkner M, et al. Downregulation of HER3: A potential surrogate for HER2 activation by heterodimerization may predict clinical benefit in ovarian cancer from pertuzumab, a HER dimerization inhibitor. Cancer Res. 2008;68(9_Supplement):4483.
Jathal MK, Chen L, Mudryj M, Ghosh PM. Targeting ErbB3: the New RTK(id) on the Prostate Cancer Block. Immunol Endocr Metab Agents Med Chem. 2011;11(2):131–49.
Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, et al. Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res. 2009;69(10):4192–201.
Osipo C, Meeke K, Cheng D, Weichel A, Bertucci A, Liu H, et al. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer. Int J Oncol. 2007;30(2):509–20.
Liu B, Ordonez-Ercan D, Fan Z, Edgerton SM, Yang X, Thor AD. Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int J Cancer. 2007;120(9):1874–82.
Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 2009;114(2):263–75.
Abel EV, Basile KJ, Kugel CH 3rd, Witkiewicz AK, Le K, Amaravadi RK, et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest. 2013;123(5):2155–68.
Montero-Conde C, Ruiz-Llorente S, Dominguez JM, Knauf JA, Viale A, Sherman EJ, et al. Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov. 2013;3(5):520–33.
Cejalvo JM, Jacob W, Fleitas Kanonnikoff T, Felip E, Navarro Mendivil A, Martinez Garcia M, et al. A phase Ib/II study of HER3-targeting lumretuzumab in combination with carboplatin and paclitaxel as first-line treatment in patients with advanced or metastatic squamous non-small cell lung cancer. ESMO Open. 2019;4(4):e000532.
Schneeweiss A, Park-Simon TW, Albanell J, Lassen U, Cortés J, Dieras V, et al. Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer. Invest New Drugs. 2018;36(5):848–59.
Kim HS, Han JY, Shin DH, Lim KY, Lee GK, Kim JY, et al. EGFR and HER3 signaling blockade in invasive mucinous lung adenocarcinoma harboring an NRG1 fusion. Lung Cancer. 2018;124:71–5.
Meulendijks D, Jacob W, Voest EE, Mau-Sorensen M, Martinez-Garcia M, Taus A, et al. Phase Ib Study of Lumretuzumab Plus Cetuximab or Erlotinib in Solid Tumor Patients and Evaluation of HER3 and Heregulin as Potential Biomarkers of Clinical Activity. Clin Cancer Res. 2017;23(18):5406–15.
Kim SB, Keam B, Shin S, Chae YS, Seo S, Park K, et al. 928P Phase I dose-expansion (part II) study of ISU104 (a novel anti-ErbB3 monoclonal antibody) alone and combination with cetuximab (CET), in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2020;31:S667–S8.
Kim SB, Keam B, Shin S, Chae YS, Seo S, Park K, et al. 928P Phase I dose-expansion (part II) study of ISU104 (a novel anti-ErbB3 monoclonal antibody) alone and combination with cetuximab (CET), in patients (pts) with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Ann Oncol. 2020;31:S667–8.
Falchook GS, Bauer TM, LoRusso P, McLaughlin JF, LaVallee T, Peck RA, et al. Safety, pharmacokinetics (PK), pharmacodynamics (Pd), and antitumor activity in a phase 1b study evaluating anti-ErbB3 antibody KTN3379 in adults with advanced tumors alone and with targeted therapies. J Clin Oncol. 2016;34(15_suppl):2501.
Duvvuri U, George J, Kim S, Alvarado D, Neumeister VM, Chenna A, et al. Molecular and Clinical Activity of CDX-3379, an Anti-ErbB3 Monoclonal Antibody, in Head and Neck Squamous Cell Carcinoma Patients. Clin Cancer Res. 2019;25(19):5752–8.
Bauman JE, Saba NF, Wise-Draper TM, Adkins D, O’Brien PE, Heath-Chiozzi M, et al. CDX3379–04: Phase II evaluation of CDX-3379 in combination with cetuximab in patients with advanced head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2019;37(15_suppl):6025.
Tchekmedyian V, Dunn L, Sherman E, Baxi SS, Grewal RK, Larson SM, et al. Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial. Thyroid. 2022;32(3):273–82.
Sarantopoulos J, Gordon MS, Harvey RD, Sankhala KK, Malik L, Mahalingam D, et al. First-in-human phase 1 dose-escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or advanced solid tumors. J Clin Oncol. 2014;32(15_suppl):11113.
Drilon A, Somwar R, Mangatt BP, Edgren H, Desmeules P, Ruusulehto A, et al. Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. Cancer Discov. 2018;8(6):686–95.
Menke-van der Houven van Oordt CW, McGeoch A, Bergstrom M, McSherry I, Smith DA, Cleveland M, et al. Immuno-PET Imaging to Assess Target Engagement: Experience from (89)Zr-Anti-HER3 mAb (GSK2849330) in Patients with Solid Tumors. J Nucl Med. 2019;60(7):902–9.
Sequist LV, Gray JE, Harb WA, Lopez-Chavez A, Doebele RC, Modiano MR, et al. Randomized Phase II Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer. Oncologist. 2019;24(8):1095–102.
Sequist LV, Janne PA, Huber RM, Gray JE, Felip E, Perol M, et al. SHERLOC: A phase 2 study of MM-121 plus with docetaxel versus docetaxel alone in patients with heregulin (HRG) positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(15_suppl):9036.
Cleary JM, McRee AJ, O’Neil BH, Sharma S, Pearlberg J, Manoli S, et al. A phase 1 study of MM-121 (a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3) in combination with cetuximab and irinotecan in patients with advanced cancers. J Clin Oncol. 2014;32(15_suppl):3076.
Cleary JM, McRee AJ, Shapiro GI, Tolaney SM, O’Neil BH, Kearns JD, et al. A phase 1 study combining the HER3 antibody seribantumab (MM-121) and cetuximab with and without irinotecan. Invest New Drugs. 2017;35(1):68–78.
Liu J, Ray-Coquard IL, Selle F, Poveda A, Cibula D, Hirte HW, et al. A phase II randomized open-label study of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with weekly paclitaxel versus weekly paclitaxel in patients with platinum-resistant/refractory ovarian cancers. J Clin Oncol. 2014;32(15_suppl):5519.
Liu JF, Ray-Coquard I, Selle F, Poveda AM, Cibula D, Hirte H, et al. Randomized Phase II Trial of Seribantumab in Combination With Paclitaxel in Patients With Advanced Platinum-Resistant or -Refractory Ovarian Cancer. J Clin Oncol. 2016;34(36):4345–53.
Higgins MJ, Doyle C, Paepke S, Azaro A, Martin M, Semiglazov V, et al. A randomized, double-blind phase II trial of exemestane plus MM-121 (a monoclonal antibody targeting ErbB3) or placebo in postmenopausal women with locally advanced or metastatic ER+/PR+, HER2-negative breast cancer. J Clin Oncol. 2014;32(15_suppl):587.
Arnedos M, Denlinger CS, Harb WA, Rixe O, Morris JC, Dy GK, et al. A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors. J Clin Oncol. 2013;31(15_suppl):2609.
Papadopoulos KP, Moore KN, Lush R, Desai M, Mahmood S, Beckman RA, et al. Pharmacokinetics, safety, and tolerability of a new patritumab formulation in patients with advanced, refractory solid tumors. J Clin Oncol. 2015;33(15_suppl):e14026-e.
Forster MD, Dillon MT, Kocsis J, Remenár É, Pajkos G, Rolland F, et al. Patritumab or placebo, with cetuximab plus platinum therapy in recurrent or metastatic squamous cell carcinoma of the head and neck: A randomised phase II study. Eur J Cancer. 2019;123:36–47.
Pawel JV, Tseng J, Dediu M, Schumann C, Moritz B, Mendell-Harary J, et al. Phase 2 HERALD study of patritumab (P) with erlotinib (E) in advanced NSCLC subjects (SBJs). J Clin Oncol. 2014;32(15_suppl):8045.
Dillon MT, Grove L, Newbold KL, Shaw H, Brown NF, Mendell J, et al. Patritumab with Cetuximab plus Platinum-Containing Therapy in Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck: An Open-Label. Phase Ib Study Clin Cancer Res. 2019;25(2):487–95.
Lockhart AC, Liu Y, Dehdashti F, Laforest R, Picus J, Frye J, et al. Phase 1 Evaluation of [(64)Cu]DOTA-Patritumab to Assess Dosimetry, Apparent Receptor Occupancy, and Safety in Subjects with Advanced Solid Tumors. Mol Imaging Biol. 2016;18(3):446–53.
LoRusso P, Janne PA, Oliveira M, Rizvi N, Malburg L, Keedy V, et al. Phase I study of U3–1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 2013;19(11):3078–87.
Im S-A, Juric D, Baselga J, Kong A, Martin P, Lin C-C, et al. A phase 1 dose-escalation study of anti-HER3 monoclonal antibody LJM716 in combination with trastuzumab in patients with HER2-overexpressing metastatic breast or gastric cancer. J Clin Oncol. 2014;32(15_suppl):2519.
Shah PD, Chandarlapaty S, Dickler MN, Ulaner G, Zamora SJ, Sterlin V, et al. Phase I study of LJM716, BYL719, and trastuzumab in patients (pts) with HER2-amplified (HER2+) metastatic breast cancer (MBC). J Clin Oncol. 2015;33(15_suppl):590.
Reynolds KL, Bedard PL, Lee SH, Lin CC, Tabernero J, Alsina M, et al. A phase I open-label dose-escalation study of the anti-HER3 monoclonal antibody LJM716 in patients with advanced squamous cell carcinoma of the esophagus or head and neck and HER2-overexpressing breast or gastric cancer. BMC Cancer. 2017;17(1):646.
Takahashi S, Kobayashi T, Tomomatsu J, Ito Y, Oda H, Kajitani T, et al. LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer. Cancer Chemother Pharmacol. 2017;79(1):131–8.
Papadopoulos KP, Adjei AA, Rasco DW, Liu L, Kao RJ, Brownstein CM, et al. Phase 1 study of REGN1400 (anti-ErbB3) combined with erlotinib or cetuximab in patients (pts) with advanced non-small cell lung cancer (NSCLC), colorectal cancer (CRC), or head and neck cancer (SCCHN). J Clin Oncol. 2014;32(15_suppl):2516.
Mirschberger C, Schiller CB, Schraml M, Dimoudis N, Friess T, Gerdes CA, et al. RG7116, a therapeutic antibody that binds the inactive HER3 receptor and is optimized for immune effector activation. Cancer Res. 2013;73(16):5183–94.
Collins D, Jacob W, Cejalvo JM, Ceppi M, James I, Hasmann M, et al. Direct estrogen receptor (ER) / HER family crosstalk mediating sensitivity to lumretuzumab and pertuzumab in ER+ breast cancer. PLoS ONE. 2017;12(5):e0177331.
Kim M, Hur Y, Seo S, Lim H, Kim K, Sohn Y, et al. Abstract 830: ISU104, a fully human antibody targeting a specific epitope on the ErbB3, displays potent inhibition of tumor growth in multiple xenograft tumor models. Cancer Res. 2018;78(13_Supplement):830.
Hong M, Yoo Y, Kim M, Kim JY, Cha JS, Choi MK, et al. A Novel Therapeutic Anti-Erb B3, ISU104 Exhibits Potent Antitumorigenic Activity by Inhibiting Ligand Binding and ErbB3 Heterodimerization. Mol Cancer Ther. 2021;20(6):1142–52.
Kim M, Hur Y, Hong M, Sohn Y, Shin K-J, Kim K, et al. Abstract 836: ISU104, a fully human anti-ErbB3 antibody, overcomes acquired cetuximab resistance. Cancer Res. 2018;78(13_Supplement):836.
Hong S-B, Hong M, Kim T-E, Kim JY, Kim JW, Cho J, et al. Abstract 3042: Anti-cancer efficacy of an anti-ErbB3 antibody, ISU104, against the cancers with NRG1-overexpression, NRG1-fusion, or oncogenic ErbB3 mutations. Cancer Res. 2020;80(16_Supplement):3042.
Lee S, Greenlee EB, Amick JR, Ligon GF, Lillquist JS, Natoli EJ Jr, et al. Inhibition of ErbB3 by a monoclonal antibody that locks the extracellular domain in an inactive configuration. Proc Natl Acad Sci U S A. 2015;112(43):13225–30.
Xiao Z, Carrasco RA, Schifferli K, Kinneer K, Tammali R, Chen H, et al. A Potent HER3 Monoclonal Antibody That Blocks Both Ligand-Dependent and -Independent Activities: Differential Impacts of PTEN Status on Tumor Response. Mol Cancer Ther. 2016;15(4):689–701.
Dall’Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006;281(33):23514–24.
Alvarado D, Ligon GF, Lillquist JS, Seibel SB, Wallweber G, Neumeister VM, et al. ErbB activation signatures as potential biomarkers for anti-ErbB3 treatment in HNSCC. PLoS ONE. 2017;12(7):e0181356.
Meister KS, Godse NR, Khan NI, Hedberg ML, Kemp C, Kulkarni S, et al. HER3 targeting potentiates growth suppressive effects of the PI3K inhibitor BYL719 in pre-clinical models of head and neck squamous cell carcinoma. Sci Rep. 2019;9(1):9130.
Vincent S, Fleet C, Bottega S, McIntosh D, Winston W, Chen T, et al. Abstract 2509: AV-203, a humanized ERBB3 inhibitory antibody inhibits ligand-dependent and ligand-independent ERBB3 signaling in vitro and in vivo. Cancer Res. 2012;72(8_Supplement):2509.
Meetze K, Vincent S, Tyler S, Mazsa EK, Delpero AR, Bottega S, et al. Neuregulin 1 expression is a predictive biomarker for response to AV-203, an ERBB3 inhibitory antibody, in human tumor models. Clin Cancer Res. 2015;21(5):1106–14.
Liao H, Zhang C, Chen Z, Gao Y, Li Z, Wang L, et al. CAN017, a novel anti-HER3 antibody, exerted great potency in mouse avatars of esophageal squamous cell carcinoma with NRG1 as a biomarker. Am J Cancer Res. 2021;11(4):1697–708.
Clarke N, Hopson C, Hahn A, Sully K, Germaschewski F, Yates J, et al. 300 Preclinical pharmacologic characterization of GSK2849330, a monoclonal AccretaMab® antibody with optimized ADCC and CDC activity directed against HER3. Eur J Cancer. 2014;50(50):98–9.
Alsaid H, Skedzielewski T, Rambo MV, Hunsinger K, Hoang B, Fieles W, et al. Non invasive imaging assessment of the biodistribution of GSK2849330, an ADCC and CDC optimized anti HER3 mAb, and its role in tumor macrophage recruitment in human tumor-bearing mice. PLoS ONE. 2017;12(4):e0176075.
Gan HK, Millward M, Jalving M, Garrido-Laguna I, Lickliter JD, Schellens JHM, et al. A Phase I, First-in-Human Study of GSK2849330, an Anti-HER3 Monoclonal Antibody, in HER3-Expressing Solid Tumors. Oncologist. 2021;26(10):e1844–53.
Liles JS, Arnoletti JP, Kossenkov AV, Mikhaylina A, Frost AR, Kulesza P, et al. Targeting ErbB3-mediated stromal-epithelial interactions in pancreatic ductal adenocarcinoma. Br J Cancer. 2011;105(4):523–33.
Schoeberl B, Pace EA, Fitzgerald JB, Harms BD, Xu L, Nie L, et al. Therapeutically targeting ErbB3: a key node in ligand-induced activation of the ErbB receptor-PI3K axis. Sci Signal. 2009;2(77):ra31.
Schoeberl B, Faber AC, Li D, Liang MC, Crosby K, Onsum M, et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res. 2010;70(6):2485–94.
Schoeberl B, Kudla A, Masson K, Kalra A, Curley M, Finn G, et al. Systems biology driving drug development: from design to the clinical testing of the anti-ErbB3 antibody seribantumab (MM-121). NPJ Syst Biol Appl. 2017;3(1):16034.
Odintsov I, Lui AJW, Sisso WJ, Gladstone E, Liu Z, Delasos L, et al. The Anti-HER3 mAb Seribantumab Effectively Inhibits Growth of Patient-Derived and Isogenic Cell Line and Xenograft Models with Oncogenic NRG1 Fusions. Clin Cancer Res. 2021;27(11):3154–66.
Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, et al. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer. 2013;12(1):134.
Wang S, Huang J, Lyu H, Cai B, Yang X, Li F, et al. Therapeutic targeting of erbB3 with MM-121/SAR256212 enhances antitumor activity of paclitaxel against erbB2-overexpressing breast cancer. Breast Cancer Res. 2013;15(5):R101.
Curley MD, Sabnis GJ, Wille L, Adiwijaya BS, Garcia G, Moyo V, et al. Seribantumab, an Anti-ERBB3 Antibody, Delays the Onset of Resistance and Restores Sensitivity to Letrozole in an Estrogen Receptor-Positive Breast Cancer Model. Mol Cancer Ther. 2015;14(11):2642–52.
Jiang N, Wang D, Hu Z, Shin HJ, Qian G, Rahman MA, et al. Combination of anti-HER3 antibody MM-121/SAR256212 and cetuximab inhibits tumor growth in preclinical models of head and neck squamous cell carcinoma. Mol Cancer Ther. 2014;13(7):1826–36.
Wang D, Qian G, Zhang H, Magliocca KR, Nannapaneni S, Amin AR, et al. HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models. Clin Cancer Res. 2017;23(3):677–86.
Treder M, Ogbagabriel S, Moor R, Schulze-Horsel U, Hettmann T, Rothe M, et al. 309 POSTER Fully human anti-HER3 mAb U3–1287 (AMG 888) demonstrates unique in vitro and in vivo activities versus other HER family inhibitors in NSCLC models. EJC Suppl. 2008;6(12):99.
Freeman D, Ogbagabriel S, Rothe M, Radinsky R, Treder M. Fully human Anti-HER3 monoclonal antibodies (mAbs) have unique in vitro and in vivo functional and antitumor activities versus other HER family inhibitors. Cancer Res. 2008;68(9_Supplement):LB-21-LB.
Yonesaka K, Hirotani K, Kawakami H, Takeda M, Kaneda H, Sakai K, et al. Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. Oncogene. 2016;35(7):878–86.
Freeman DJ, Ogbagabriel S, Bready J, Sun J-R, Radinsky R, Hettmann T. Abstract A182: U3–1287 (AMG 888), a fully human anti-HER3 mAb, demonstrates in vitro and in vivo efficacy in the FaDu model of human squamous cell carcinoma of the head and neck (SCCHN). Molecular Cancer Therapeutics. 2011;10(11_supplement):A182-A.
Li C, Brand TM, Iida M, Huang S, Armstrong EA, van der Kogel A, et al. Human epidermal growth factor receptor 3 (HER3) blockade with U3–1287/AMG888 enhances the efficacy of radiation therapy in lung and head and neck carcinoma. Discov Med. 2013;16(87):79–92.
Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, et al. The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget. 2014;5(23):11847–56.
Garrett JT, Sutton CR, Kuba MG, Cook RS, Arteaga CL. Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin Cancer Res. 2013;19(3):610–9.
Bandyopadhyay A, Favours E, Phelps DA, Pozo VD, Ghilu S, Kurmashev D, et al. Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models. Pediatr Blood Cancer. 2018;65(2):e26870.
Mukai H, Saeki T, Aogi K, Naito Y, Matsubara N, Shigekawa T, et al. Patritumab plus trastuzumab and paclitaxel in human epidermal growth factor receptor 2-overexpressing metastatic breast cancer. Cancer Sci. 2016;107(10):1465–70.
Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, et al. An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res. 2013;73(19):6024–35.
Garrett JT, Sutton CR, Kurupi R, Bialucha CU, Ettenberg SA, Collins SD, et al. Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. Cancer Res. 2013;73(19):6013–23.
Jhaveri K, Drago JZ, Shah PD, Wang R, Pareja F, Ratzon F, et al. A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer. Clin Cancer Res. 2021;27(14):3867–75.
Zhang L, Castanaro C, Luan B, Yang K, Fan L, Fairhurst JL, et al. ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models. Mol Cancer Ther. 2014;13(5):1345–55.
Zhang L, Luan B, Yang K, Castanaro C, Papadopoulos N, Thurston G, et al. Abstract 2718: REGN1400, a fully-human ERBB3 antibody, potently inhibits tumor growth in preclinical models, both as a monotherapy and in combination with EGFR or HER2 blockers. Cancer Research. 2012;72(8_Supplement):2718.
Jacobsen HJ, Poulsen TT, Dahlman A, Kjaer I, Koefoed K, Sen JW, et al. Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity. Clin Cancer Res. 2015;21(18):4110–22.
Schwarz LJ, Hutchinson KE, Rexer BN, Estrada MV, Gonzalez Ericsson PI, Sanders ME, et al. An ERBB1–3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression. J Natl Cancer Inst. 2017;109(11). https://doi.org/10.1093/jnci/djx065.
Francis DM, Huang S, Armstrong EA, Werner LR, Hullett C, Li C, et al. Pan-HER Inhibitor Augments Radiation Response in Human Lung and Head and Neck Cancer Models. Clin Cancer Res. 2016;22(3):633–43.
Iida M, Bahrar H, Brand TM, Pearson HE, Coan JP, Orbuch RA, et al. Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab. Mol Cancer Ther. 2016;15(9):2175–86.
Rabia E, Garambois V, Hubert J, Bruciamacchie M, Pirot N, Delpech H, et al. Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models. MAbs. 2021;13(1):1914883.
Berlin J, Tolcher AW, Ding C, Whisenant JG, Horak ID, Wood DL, et al. First-in-human trial exploring safety, antitumor activity, and pharmacokinetics of Sym013, a recombinant pan-HER antibody mixture, in advanced epithelial malignancies. Invest New Drugs. 2022;40(3):586–95.
Aurisicchio L, Marra E, Luberto L, Carlomosti F, De Vitis C, Noto A, et al. Novel anti-ErbB3 monoclonal antibodies show therapeutic efficacy in xenografted and spontaneous mouse tumors. J Cell Physiol. 2012;227(10):3381–8.
Aurisicchio L, Marra E, Roscilli G, Mancini R, Ciliberto G. The promise of anti-ErbB3 monoclonals as new cancer therapeutics. Oncotarget. 2012;3(8):744–58.
Belleudi F, Marra E, Mazzetta F, Fattore L, Giovagnoli MR, Mancini R, et al. Monoclonal antibody-induced ErbB3 receptor internalization and degradation inhibits growth and migration of human melanoma cells. Cell Cycle. 2012;11(7):1455–67.
Fattore L, Malpicci D, Marra E, Belleudi F, Noto A, De Vitis C, et al. Combination of antibodies directed against different ErbB3 surface epitopes prevents the establishment of resistance to BRAF/MEK inhibitors in melanoma. Oncotarget. 2015;6(28):24823–41.
Noto A, De Vitis C, Roscilli G, Fattore L, Malpicci D, Marra E, et al. Combination therapy with anti-ErbB3 monoclonal antibodies and EGFR TKIs potently inhibits non-small cell lung cancer. Oncotarget. 2013;4(8):1253–65.
Ciardiello C, Roca MS, Noto A, Bruzzese F, Moccia T, Vitagliano C, et al. Synergistic antitumor activity of histone deacetylase inhibitors and anti-ErbB3 antibody in NSCLC primary cultures via modulation of ErbB receptors expression. Oncotarget. 2016;7(15):19559–74.
Sala G, Traini S, D’Egidio M, Vianale G, Rossi C, Piccolo E, et al. An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. Oncogene. 2012;31(10):1275–86.
Sala G, Rapposelli IG, Ghasemi R, Piccolo E, Traini S, Capone E, et al. EV20, a Novel Anti-ErbB-3 Humanized Antibody, Promotes ErbB-3 Down-Regulation and Inhibits Tumor Growth In Vivo. Transl Oncol. 2013;6(6):676–84.
Rajkumar T, Gullick WJ. A monoclonal antibody to the human c-erbB3 protein stimulates the anchorage-independent growth of breast cancer cell lines. Br J Cancer. 1994;70(3):459–65.
Blackburn E, Zona S, Murphy ML, Brown IR, Chan SK, Gullick WJ. A monoclonal antibody to the human HER3 receptor inhibits Neuregulin 1-beta binding and co-operates with Herceptin in inhibiting the growth of breast cancer derived cell lines. Breast Cancer Res Treat. 2012;134(1):53–9.
Leung WY, Roxanis I, Sheldon H, Buffa FM, Li JL, Harris AL, et al. Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer. Oncotarget. 2015;6(8):5678–94.
Lazrek Y, Dubreuil O, Garambois V, Gaborit N, Larbouret C, Le Clorennec C, et al. Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation. Neoplasia. 2013;15(3):335–47.
Thomas G, Chardes T, Gaborit N, Mollevi C, Leconet W, Robert B, et al. HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models. Oncotarget. 2014;5(16):7138–48.
Le Clorennec C, Bazin H, Dubreuil O, Larbouret C, Ogier C, Lazrek Y, et al. Neuregulin 1 Allosterically Enhances the Antitumor Effects of the Noncompeting Anti-HER3 Antibody 9F7-F11 by Increasing Its Binding to HER3. Mol Cancer Ther. 2017;16(7):1312–23.
Okita K, Okazaki S, Uejima S, Yamada E, Kaminaka H, Kondo M, et al. Novel functional anti-HER3 monoclonal antibodies with potent anti-cancer effects on various human epithelial cancers. Oncotarget. 2020;11(1):31–45.
Chen X, Levkowitz G, Tzahar E, Karunagaran D, Lavi S, Ben-Baruch N, et al. An immunological approach reveals biological differences between the two NDF/heregulin receptors, ErbB-3 and ErbB-4. J Biol Chem. 1996;271(13):7620–9.
van der Horst EH, Murgia M, Treder M, Ullrich A. Anti-HER-3 MAbs inhibit HER-3-mediated signaling in breast cancer cell lines resistant to anti-HER-2 antibodies. Int J Cancer. 2005;115(4):519–27.
Gaborit N, Abdul-Hai A, Mancini M, Lindzen M, Lavi S, Leitner O, et al. Examination of HER3 targeting in cancer using monoclonal antibodies. Proc Natl Acad Sci U S A. 2015;112(3):839–44.
Romaniello D, Marrocco I, Belugali Nataraj N, Ferrer I, Drago-Garcia D, Vaknin I, et al. Targeting HER3, a Catalytically Defective Receptor Tyrosine Kinase, Prevents Resistance of Lung Cancer to a Third-Generation EGFR Kinase Inhibitor. Cancers (Basel). 2020;12(9). https://doi.org/10.3390/cancers12092394.
Mancini M, Gal H, Gaborit N, Mazzeo L, Romaniello D, Salame TM, et al. An oligoclonal antibody durably overcomes resistance of lung cancer to third-generation EGFR inhibitors. EMBO Mol Med. 2018;10(2):294–308.
Mancini M, Gaborit N, Lindzen M, Salame TM, Dall’Ora M, Sevilla-Sharon M, et al. Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. Sci Signal. 2015;8(379):ra53.
Wang Q, Zhang X, Shen E, Gao J, Cao F, Wang X, et al. The anti-HER3 antibody in combination with trastuzumab exerts synergistic antitumor activity in HER2-positive gastric cancer. Cancer Lett. 2016;380(1):20–30.
Li X, Duan Y, Qiao C, Zhou T, Yu M, Geng J, et al. Anti-HER3 Monoclonal Antibody Inhibits Acquired Trastuzumab-Resistant Gynecologic Cancers. Technol Cancer Res Treat. 2016;15(4):573–82.
Turowec JP, Lau EWT, Wang X, Brown KR, Fellouse FA, Jawanda KK, et al. Functional genomic characterization of a synthetic anti-HER3 antibody reveals a role for ubiquitination by RNF41 in the anti-proliferative response. J Biol Chem. 2019;294(4):1396–409.
Setiady YY, Skaletskaya A, Coccia J, Moreland J, Carrigan C, Rui L, et al. Abstract 4564: huHER3–8, a novel humanized anti-HER3 antibody that inhibits exogeneous ligand-independent proliferation of tumor cells. Cancer Res. 2011;71(8_Supplement):4564.
Kugel CH 3rd, Hartsough EJ, Davies MA, Setiady YY, Aplin AE. Function-blocking ERBB3 antibody inhibits the adaptive response to RAF inhibitor. Cancer Res. 2014;74(15):4122–32.
Capparelli C, Rosenbaum S, Berman-Booty LD, Salhi A, Gaborit N, Zhan T, et al. ErbB3-ErbB2 Complexes as a Therapeutic Target in a Subset of Wild-type BRAF/NRAS Cutaneous Melanomas. Cancer Res. 2015;75(17):3554–67.
Moller Y, Morkel M, Schmid J, Beyes S, Hendrick J, Strotbek M, et al. Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling. Oncotarget. 2016;7(33):53526–39.
Schmitt LC, Rau A, Seifert O, Honer J, Hutt M, Schmid S, et al. Inhibition of HER3 activation and tumor growth with a human antibody binding to a conserved epitope formed by domain III and IV. MAbs. 2017;9(5):831–43.
Asano T, Ohishi T, Takei J, Nakamura T, Nanamiya R, Hosono H, et al. AntiHER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma. Oncol Rep. 2021;46(2). https://doi.org/10.3892/or.2021.8124.
Hassani D, Jeddi-Tehrani M, Yousefi P, Mansouri-Fard S, Mobini M, Ahmadi-Zare H, et al. Differential tumor inhibitory effects induced by HER3 extracellular subdomain-specific mouse monoclonal antibodies. Cancer Chemother Pharmacol. 2022;89(3):347–61.
Eliseev IE, Ukrainskaya VM, Yudenko AN, Mikushina AD, Shmakov SV, Afremova AI, et al. Targeting ErbB3 Receptor in Cancer with Inhibitory Antibodies from Llama. Biomedicines. 2021;9(9). https://doi.org/10.3390/biomedicines9091106.
Alsina M, Boni V, Schellens JHM, Moreno V, Bol K, Westendorp M, et al. First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3: Final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC). J Clin Oncol. 2017;35(15_suppl):2522.
Hamilton EP, Petit T, Pistilli B, Goncalves A, Ferreira AA, Dalenc F, et al. Clinical activity of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in HER2 amplified metastatic breast cancer (MBC) patients (pts) who had progressed on anti-HER2 ADCs. J Clin Oncol. 2020;38(15_suppl):3093.
Richards DA, Braiteh FS, Garcia AA, Denlinger CS, Conkling PR, Edenfield WJ, et al. A phase 1 study of MM-111, a bispecific HER2/HER3 antibody fusion protein, combined with multiple treatment regimens in patients with advanced HER2-positive solid tumors. J Clin Oncol. 2014;32(15_suppl):651.
Denlinger CS, Maqueda MA, Watkins DJ, Sym SJ, Bendell JC, Park SH, et al. Randomized phase 2 study of paclitaxel (PTX), trastuzumab (T) with or without MM-111 in HER2 expressing gastroesophageal cancers (GEC). J Clin Oncol. 2016;34(15_suppl):4043.
Isakoff S, Bahleda R, Saleh M, Bordoni R, Shields A, Dauer J, et al. 420 - A phase 1 study of MM-141, a novel tetravalent monoclonal antibody targeting IGF-1R and ErbB3, in relapsed or refractory solid tumors. Eur J Cancer. 2016;69:S137–8.
Kundranda M, Gracian AC, Zafar SF, Meiri E, Bendell J, Algul H, et al. Randomized, double-blind, placebo-controlled phase II study of istiratumab (MM-141) plus nab-paclitaxel and gemcitabine versus nab-paclitaxel and gemcitabine in front-line metastatic pancreatic cancer (CARRIE). Ann Oncol. 2020;31(1):79–87.
Lieu CH, Hidalgo M, Berlin JD, Ko AH, Cervantes A, LoRusso P, et al. A Phase Ib Dose-Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and Duligotuzumab in Patients with Previously Treated Locally Advanced or Metastatic Cancers with Mutant KRAS. Oncologist. 2017;22(9):1024-e89.
Juric D, Dienstmann R, Cervantes A, Hidalgo M, Messersmith W, Blumenschein GR Jr, et al. Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors. Clin Cancer Res. 2015;21(11):2462–70.
Jimeno A, Machiels JP, Wirth L, Specenier P, Seiwert TY, Mardjuadi F, et al. Phase Ib study of duligotuzumab (MEHD7945A) plus cisplatin/5-fluorouracil or carboplatin/paclitaxel for first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck. Cancer. 2016;122(24):3803–11.
Hill AG, Findlay MP, Burge ME, Jackson C, Alfonso PG, Samuel L, et al. Phase II Study of the Dual EGFR/HER3 Inhibitor Duligotuzumab (MEHD7945A) versus Cetuximab in Combination with FOLFIRI in Second-Line RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res. 2018;24(10):2276–84.
Fayette J, Wirth L, Oprean C, Udrea A, Jimeno A, Rischin D, et al. Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study). Front Oncol. 2016;6:232.
Geuijen CAW, De Nardis C, Maussang D, Rovers E, Gallenne T, Hendriks LJA, et al. Unbiased Combinatorial Screening Identifies a Bispecific IgG1 that Potently Inhibits HER3 Signaling via HER2-Guided Ligand Blockade. Cancer Cell. 2018;33(5):922-36 e10.
Schram AM, Odintsov I, Espinosa-Cotton M, Khodos I, Sisso WJ, Mattar MS, et al. Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer Discov. 2022;12(5):1233–47.
Gao Z, Tan P, Kovacevich BR, Renshaw BR, Adamo JB, Mak NSA, et al. Bispecific Tetravalent Antibodies and Methods of Making and Using Thereof. Google Patents; 2017.
Xue J, Kong D, Yao Y, Yang L, Yao Q, Zhu Y, et al. Prediction of Human Pharmacokinetics and Clinical Effective Dose of SI-B001, an EGFR/HER3 Bi-specific Monoclonal Antibody. J Pharm Sci. 2020;109(10):3172–80.
McDonagh CF, Huhalov A, Harms BD, Adams S, Paragas V, Oyama S, et al. Antitumor activity of a novel bispecific antibody that targets the ErbB2/ErbB3 oncogenic unit and inhibits heregulin-induced activation of ErbB3. Mol Cancer Ther. 2012;11(3):582–93.
Zhang B, Lahdenranta J, Du J, Kirouac D, Nguyen S, Overland R, et al. Abstract 4633: MM-111, a bispecific HER2 and HER3 antibody, synergistically combines with trastuzumab and paclitaxel in preclinical models of gastric cancer. Cancer Res. 2013;73(8_Supplement):4633.
Fitzgerald JB, Johnson BW, Baum J, Adams S, Iadevaia S, Tang J, et al. MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol Cancer Ther. 2014;13(2):410–25.
Camblin AJ, Tan G, Curley MD, Yannatos I, Iadevaia S, Rimkunas V, et al. Dual targeting of IGF-1R and ErbB3 as a potential therapeutic regimen for ovarian cancer. Sci Rep. 2019;9(1):16832.
Von Euw EM, Pace E, Covarrubias K, Jairam A, Chai D, Konkankit V, et al. Abstract 2077A: MM141, a novel bispecific antibody co-inhibitor of IGF-1R and ErbB3, inhibits the proliferation of melanoma cells. Cancer Res. 2013;73(8_Supplement):2077A-A.
Camblin AJ, Pace EA, Adams S, Curley MD, Rimkunas V, Nie L, et al. Dual Inhibition of IGF-1R and ErbB3 Enhances the Activity of Gemcitabine and Nab-Paclitaxel in Preclinical Models of Pancreatic Cancer. Clin Cancer Res. 2018;24(12):2873–85.
Crocker LM, Fields C, Shao L, Sliwkowski MX, Phillips GDL, Schaefer G. Abstract 1212: The dual action antibody MEHD7945A targeting EGFR and HER3 enhances chemotherapy induced cytotoxicity in vitro and in vivo. Cancer Res. 2012;72(8_Supplement):1212.
Schaefer G, Haber L, Crocker LM, Shia S, Shao L, Dowbenko D, et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell. 2011;20(4):472–86.
Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, et al. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res. 2013;73(2):824–33.
De Pauw I, Wouters A, Van den Bossche J, Deschoolmeester V, Baysal H, Pauwels P, et al. Dual Targeting of Epidermal Growth Factor Receptor and HER3 by MEHD7945A as Monotherapy or in Combination with Cisplatin Partially Overcomes Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cell Lines. Cancer Biother Radiopharm. 2017;32(7):229–38.
Tao JJ, Castel P, Radosevic-Robin N, Elkabets M, Auricchio N, Aceto N, et al. Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci Signal. 2014;7(318):ra29.
Laterza MM, Ciaramella V, Facchini BA, Franzese E, Liguori C, De Falco S, et al. Enhanced Antitumor Effect of Trastuzumab and Duligotuzumab or Ipatasertib Combination in HER-2 Positive Gastric Cancer Cells. Cancers (Basel). 2021;13(10). https://doi.org/10.3390/cancers13102339.
Bourillon L, Demontoy S, Lenglet A, Zampieri A, Fraisse J, Jarlier M, et al. Higher Anti-Tumor Efficacy of the Dual HER3-EGFR Antibody MEHD7945a Combined with Ionizing Irradiation in Cervical Cancer Cells. Int J Radiat Oncol Biol Phys. 2020;106(5):1039–51.
Kang JC, Poovassery JS, Bansal P, You S, Manjarres IM, Ober RJ, et al. Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. MAbs. 2014;6(2):340–53.
Poovassery JS, Kang JC, Kim D, Ober RJ, Ward ES. Antibody targeting of HER2/HER3 signaling overcomes heregulin-induced resistance to PI3K inhibition in prostate cancer. Int J Cancer. 2015;137(2):267–77.
D’Souza JW, Reddy S, Goldsmith LE, Shchaveleva I, Marks JD, Litwin S, et al. Combining anti-ERBB3 antibodies specific for domain I and domain III enhances the anti-tumor activity over the individual monoclonal antibodies. PLoS ONE. 2014;9(11):e112376.
Gu J, Yang J, Chang Q, Liu Z, Ghayur T, Gu J. Identification of Anti-EGFR and Anti-ErbB3 Dual Variable Domains Immunoglobulin (DVD-Ig) Proteins with Unique Activities. PLoS ONE. 2015;10(5):e0124135.
Rau A, Lieb WS, Seifert O, Honer J, Birnstock D, Richter F, et al. Inhibition of Tumor Cell Growth and Cancer Stem Cell Expansion by a Bispecific Antibody Targeting EGFR and HER3. Mol Cancer Ther. 2020;19(7):1474–85.
Rau A, Janssen N, Kuhl L, Sell T, Kalmykova S, Murdter TE, et al. Triple Targeting of HER Receptors Overcomes Heregulin-mediated Resistance to EGFR Blockade in Colorectal Cancer. Mol Cancer Ther. 2022;21(5):799–809.
Rau A, Kocher K, Rommel M, Kuhl L, Albrecht M, Gotthard H, et al. A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3. MAbs. 2021;13(1):1902034.
Aschmoneit N, Steinlein S, Kuhl L, Seifert O, Kontermann RE. A scDb-based trivalent bispecific antibody for T-cell-mediated killing of HER3-expressing cancer cells. Sci Rep. 2021;11(1):13880.
Aschmoneit N, Kuhl L, Seifert O, Kontermann RE. Fc-comprising scDb-based trivalent, bispecific T-cell engagers for selective killing of HER3-expressing cancer cells independent of cytokine release. J Immunother Cancer. 2021;9(11). https://doi.org/10.1136/jitc-2021-003616.
Hassani D, Amiri MM, Mohammadi M, Yousefi P, Judaki MA, Mobini M, et al. A novel tumor inhibitory hybridoma monoclonal antibody with dual specificity for HER3 and HER2. Curr Res Transl Med. 2021;69(2):103277.
Gandullo-Sanchez L, Ocana A, Pandiella A. Generation of Antibody-Drug Conjugate Resistant Models. Cancers (Basel). 2021;13(18). https://doi.org/10.3390/cancers13184631.
Garcia-Alonso S, Ocana A, Pandiella A. Resistance to Antibody-Drug Conjugates. Cancer Res. 2018;78(9):2159–65.
Hashimoto Y, Koyama K, Kamai Y, Hirotani K, Ogitani Y, Zembutsu A, et al. A Novel HER3-Targeting Antibody-Drug Conjugate, U3–1402, Exhibits Potent Therapeutic Efficacy through the Delivery of Cytotoxic Payload by Efficient Internalization. Clin Cancer Res. 2019;25(23):7151–61.
Koganemaru S, Kuboki Y, Koga Y, Kojima T, Yamauchi M, Maeda N, et al. U3–1402, a Novel HER3-Targeting Antibody-Drug Conjugate, for the Treatment of Colorectal Cancer. Mol Cancer Ther. 2019;18(11):2043–50.
Haikala HM, Lopez T, Kohler J, Eser PO, Xu M, Zeng Q, et al. EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd. Cancer Res. 2022;82(1):130–41.
Yonesaka K, Tanizaki J, Maenishi O, Haratani K, Kawakami H, Tanaka K, et al. HER3 Augmentation via Blockade of EGFR/AKT Signaling Enhances Anticancer Activity of HER3-Targeting Patritumab Deruxtecan in EGFR-Mutated Non-Small Cell Lung Cancer. Clin Cancer Res. 2022;28(2):390–403.
Yonesaka K, Takegawa N, Watanabe S, Haratani K, Kawakami H, Sakai K, et al. An HER3-targeting antibody-drug conjugate incorporating a DNA topoisomerase I inhibitor U3–1402 conquers EGFR tyrosine kinase inhibitor-resistant NSCLC. Oncogene. 2019;38(9):1398–409.
Haratani K, Yonesaka K, Takamura S, Maenishi O, Kato R, Takegawa N, et al. U3–1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation. J Clin Invest. 2020;130(1):374–88.
Janne PA, Baik C, Su WC, Johnson ML, Hayashi H, Nishio M, et al. Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor-Resistant, EGFR-Mutated Non-Small Cell Lung Cancer. Cancer Discov. 2022;12(1):74–89.
Yu HA, Baik CS, Gold K, Hayashi H, Johnson M, Koczywas M, et al. LBA62 Efficacy and safety of patritumab deruxtecan (U3–1402), a novel HER3 directed antibody drug conjugate, in patients (pts) with EGFR-mutated (EGFRm) NSCLC. Ann Oncol. 2020;31:S1189–90.
Masuda N, Yonemori K, Takahashi S, Kogawa T, Nakayama T, Iwase H, et al. Abstract PD1–03: Single agent activity of U3–1402, a HER3-targeting antibody-drug conjugate, in HER3-overexpressing metastatic breast cancer: Updated results of a phase 1/2 trial. Cancer Res. 2019;79(4_Supplement):PD1-03-PD1.
Lim SM, Kim CG, Lee JB, Cho BC. Patritumab Deruxtecan: Paving the Way for EGFR-TKI-Resistant NSCLC. Cancer Discov. 2022;12(1):16–9.
Janne PA, Yu HA, Johnson ML, Steuer CE, Vigliotti M, Iacobucci C, et al. Safety and preliminary antitumor activity of U3–1402: A HER3-targeted antibody drug conjugate in EGFR TKI-resistant, EGFRm NSCLC. J Clin Oncol. 2019;37(15_suppl):9010.
Kogawa T, Yonemori K, Masuda N, Takahashi S, Takahashi M, Iwase H, et al. Single agent activity of U3–1402, a HER3-targeting antibody-drug conjugate, in breast cancer patients: Phase 1 dose escalation study. J Clin Oncol. 2018;36(15_suppl):2512.
Capone E, Giansanti F, Ponziani S, Lamolinara A, Iezzi M, Cimini A, et al. EV20-Sap, a novel anti-HER-3 antibody-drug conjugate, displays promising antitumor activity in melanoma. Oncotarget. 2017;8(56):95412–24.
Capone E, Lamolinara A, D’Agostino D, Rossi C, De Laurenzi V, Iezzi M, et al. EV20-mediated delivery of cytotoxic auristatin MMAF exhibits potent therapeutic efficacy in cutaneous melanoma. J Control Release. 2018;277:48–56.
Gandullo-Sanchez L, Capone E, Ocana A, Iacobelli S, Sala G, Pandiella A. HER3 targeting with an antibody-drug conjugate bypasses resistance to anti-HER2 therapies. EMBO Mol Med. 2020;12(5):e11498.
D’Agostino D, Gentile R, Ponziani S, Di Vittorio G, Dituri F, Giannelli G, et al. EV20sssvc/MMAF, an HER3 targeting antibodydrug conjugate displays antitumor activity in liver cancer. Oncol Rep. 2021;45(2):776–85.
Capone E, Lattanzio R, Gasparri F, Orsini P, Rossi C, Iacobelli V, et al. EV20/NMS-P945, a Novel Thienoindole Based Antibody-Drug Conjugate Targeting HER-3 for Solid Tumors. Pharmaceutics. 2021;13(4). https://doi.org/10.3390/pharmaceutics13040483.
Bourillon L, Bourgier C, Gaborit N, Garambois V, Lles E, Zampieri A, et al. An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer. Int J Cancer. 2019;145(7):1838–51.
Hu S, Fu W, Xu W, Yang Y, Cruz M, Berezov SD, et al. Four-in-one antibodies have superior cancer inhibitory activity against EGFR, HER2, HER3, and VEGF through disruption of HER/MET crosstalk. Cancer Res. 2015;75(1):159–70.
Castoldi R, Schanzer J, Panke C, Jucknischke U, Neubert NJ, Croasdale R, et al. TetraMabs: simultaneous targeting of four oncogenic receptor tyrosine kinases for tumor growth inhibition in heterogeneous tumor cell populations. Protein Eng Des Sel. 2016;29(10):467–75.
Castoldi R, Jucknischke U, Pradel LP, Arnold E, Klein C, Scheiblich S, et al. Molecular characterization of novel trispecific ErbB-cMet-IGF1R antibodies and their antigen-binding properties. Protein Eng Des Sel. 2012;25(10):551–9.
Malm M, Frejd FY, Stahl S, Lofblom J. Targeting HER3 using mono- and bispecific antibodies or alternative scaffolds. MAbs. 2016;8(7):1195–209.
Foreman PK, Gore M, Kobel PA, Xu L, Yee H, Hannum C, et al. ErbB3 inhibitory surrobodies inhibit tumor cell proliferation in vitro and in vivo. Mol Cancer Ther. 2012;11(7):1411–20.
Lofblom J, Feldwisch J, Tolmachev V, Carlsson J, Stahl S, Frejd FY. Affibody molecules: engineered proteins for therapeutic, diagnostic and biotechnological applications. FEBS Lett. 2010;584(12):2670–80.
Leitao CD, Rinne SS, Altai M, Vorontsova O, Dunas F, Jonasson P, et al. Evaluating the Therapeutic Efficacy of Mono- and Bivalent Affibody-Based Fusion Proteins Targeting HER3 in a Pancreatic Cancer Xenograft Model. Pharmaceutics. 2020;12(6). https://doi.org/10.3390/pharmaceutics12060551.
Schardt JS, Noonan-Shueh M, Oubaid JM, Pottash AE, Williams SC, Hussain A, et al. HER3-Targeted Affibodies with Optimized Formats Reduce Ovarian Cancer Progression in a Mouse Xenograft Model. AAPS J. 2019;21(3):48.
Liu H, Jia D, Yuan F, Wang F, Wei D, Tang X, et al. Her3-specific affibody mediated tumor targeting delivery of ICG enhanced the photothermal therapy against Her3-positive tumors. Int J Pharm. 2022;617:121609.
Malm M, Bass T, Gudmundsdotter L, Lord M, Frejd FY, Stahl S, et al. Engineering of a bispecific affibody molecule towards HER2 and HER3 by addition of an albumin-binding domain allows for affinity purification and in vivo half-life extension. Biotechnol J. 2014;9(9):1215–22.
Seifert O, Rau A, Beha N, Richter F, Kontermann RE. Diabody-Ig: a novel platform for the generation of multivalent and multispecific antibody molecules. MAbs. 2019;11(5):919–29.
Haikala HM, Jänne PA. Thirty Years of HER3: From Basic Biology to Therapeutic Interventions. Clin Cancer Res. 2021;27(13):3528–39.
Kol A, Terwisscha van Scheltinga AG, Timmer-Bosscha H, Lamberts LE, Bensch F, de Vries EG, et al. HER3, serious partner in crime: therapeutic approaches and potential biomarkers for effect of HER3-targeting. Pharmacol Ther. 2014;143(1):1–11.
Osada T, Morse MA, Hobeika A, Diniz MA, Gwin WR, Hartman Z, et al. Vaccination targeting human HER3 alters the phenotype of infiltrating T cells and responses to immune checkpoint inhibition. Oncoimmunology. 2017;6(6):e1315495.
Osada T, Hartman ZC, Wei J, Lei G, Hobeika AC, Gwin WR, et al. Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers. Breast Cancer Res. 2018;20(1):90.
Miller MJ, Foy KC, Overholser JP, Nahta R, Kaumaya PT. HER-3 peptide vaccines/mimics: Combined therapy with IGF-1R, HER-2, and HER-1 peptides induces synergistic antitumor effects against breast and pancreatic cancer cells. Oncoimmunology. 2014;3(11):e956012.
Sarup J, Jin P, Turin L, Bai X, Beryt M, Brdlik C, et al. Human epidermal growth factor receptor (HER-1:HER-3) Fc-mediated heterodimer has broad antiproliferative activity in vitro and in human tumor xenografts. Mol Cancer Ther. 2008;7(10):3223–36.
Wu Y, Zhang Y, Wang M, Li Q, Qu Z, Shi V, et al. Downregulation of HER3 by a novel antisense oligonucleotide, EZN-3920, improves the antitumor activity of EGFR and HER2 tyrosine kinase inhibitors in animal models. Mol Cancer Ther. 2013;12(4):427–37.
Zhao Z, Li R, Sha S, Wang Q, Mao W, Liu T. Targeting HER3 with miR-450b-3p suppresses breast cancer cells proliferation. Cancer Biol Ther. 2014;15(10):1404–12.
Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2007;282(2):1479–86.
Iorio MV, Casalini P, Piovan C, Di Leva G, Merlo A, Triulzi T, et al. microRNA-205 regulates HER3 in human breast cancer. Cancer Res. 2009;69(6):2195–200.
Yuan HH, Yang YN, Zhou JH, Li YJ, Wang LY, Qin JW, et al. siRNA-mediated inactivation of HER3 improves the antitumour activity and sensitivity of gefitinib in gastric cancer cells. Oncotarget. 2017;8(32):52584–93.
Yu X, Ghamande S, Liu H, Xue L, Zhao S, Tan W, et al. Targeting EGFR/HER2/HER3 with a Three-in-One Aptamer-siRNA Chimera Confers Superior Activity against HER2(+) Breast Cancer. Mol Ther Nucleic Acids. 2018;10:317–30.
Shu M, Gao F, Yu C, Zeng M, He G, Wu Y, et al. Dual-targeted therapy in HER2-positive breast cancer cells with the combination of carbon dots/HER3 siRNA and trastuzumab. Nanotechnology. 2020;31(33):335102.
Xu X, Li L, Li X, Tao D, Zhang P, Gong J. Aptamer-protamine-siRNA nanoparticles in targeted therapy of ErbB3 positive breast cancer cells. Int J Pharm. 2020;590:119963.
Dou XQ, Wang H, Zhang J, Wang F, Xu GL, Xu CC, et al. Aptamer-drug conjugate: targeted delivery of doxorubicin in a HER3 aptamer-functionalized liposomal delivery system reduces cardiotoxicity. Int J Nanomedicine. 2018;13:763–76.
Ali MY, Tariq I, Farhan Sohail M, Amin MU, Ali S, Pinnapireddy SR, et al. Selective anti-ErbB3 aptamer modified sorafenib microparticles: In vitro and in vivo toxicity assessment. Eur J Pharm Biopharm. 2019;145:42–53.
Chen CH, Chernis GA, Hoang VQ, Landgraf R. Inhibition of heregulin signaling by an aptamer that preferentially binds to the oligomeric form of human epidermal growth factor receptor-3. Proc Natl Acad Sci U S A. 2003;100(16):9226–31.
Nachreiner I, Hussain AF, Wullner U, Machuy N, Meyer TF, Fischer R, et al. Elimination of HER3-expressing breast cancer cells using aptamer-siRNA chimeras. Exp Ther Med. 2019;18(4):2401–12.
Yokoyama T, Ando T, Iwamoto R, Fuji D, Yamamoto M, Kawakami T. A human epidermal growth factor receptor 3/heregulin interaction inhibitor aptamer discovered using SELEX. Biochem Biophys Res Commun. 2021;553:148–53.
Xie T, Lim SM, Westover KD, Dodge ME, Ercan D, Ficarro SB, et al. Pharmacological targeting of the pseudokinase Her3. Nat Chem Biol. 2014;10(12):1006–12.
Lim SM, Xie T, Westover KD, Ficarro SB, Tae HS, Gurbani D, et al. Development of small molecules targeting the pseudokinase Her3. Bioorg Med Chem Lett. 2015;25(16):3382–9.
Sims JD, Taguiam JM, Alonso-Valenteen F, Markman J, Agadjanian H, Chu D, et al. Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics. J Control Release. 2018;271:127–38.
Ogier C, Colombo PE, Bousquet C, Canterel-Thouennon L, Sicard P, Garambois V, et al. Targeting the NRG1/HER3 pathway in tumor cells and cancer-associated fibroblasts with an anti-neuregulin 1 antibody inhibits tumor growth in pre-clinical models of pancreatic cancer. Cancer Lett. 2018;432:227–36.
Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, et al. Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer. Sci Transl Med. 2013;5(171):171ra18.
Jacob W, James I, Hasmann M, Weisser M. Clinical development of HER3-targeting monoclonal antibodies: Perils and progress. Cancer Treat Rev. 2018;68:111–23.
This work was supported by the Ministry of Economy and Competitiveness of Spain (PID2020-115605RB-I00), the Instituto de Salud Carlos III through CIBERONC, Junta de Castilla y León (CSI146P20), ALMOM, ACMUMA, UCCTA, the CRIS Cancer Foundation and the Regional Development Funding Program (FEDER) “A way to make Europe”. LGS was recipient of a predoctoral contract (BES-2016–077748); and is at present contracted by the Cancer Research Foundation of the Salamanca University (FICUS).
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Gandullo-Sánchez, L., Ocaña, A. & Pandiella, A. HER3 in cancer: from the bench to the bedside. J Exp Clin Cancer Res 41, 310 (2022). https://doi.org/10.1186/s13046-022-02515-x
- Cancer therapy
- Receptor tyrosine kinases