Table 7 Characteristic subtype-specific therapeutic vulnerabilities in TNBC
TNBC subtype | Pathway | Genetic dependency | Pharmacologic dependency | Patient-derived tumor xenograft dependency |
|---|---|---|---|---|
Luminal androgen receptor | AR signalling | AR SPDEF FOXA1 | Bicalutamide (AR) | Bicalutamide (AR) |
PI3K/AKT signalling | PIK3CA AKT1 EIF4A2 RPS6 ERBB2 | GSK690693 (AKT) ZSTK474 (PI3K) Omipalsib (PI3K/mTOR) OSI-027 (mTOR) AZD6482 (PI3Kb) | GDC0941 (PI3K) NVP-BEZ235 (PI3K/mTORC1/2) AZD8055 (mTORC1/2) Everolimus (mTOR) | |
Other | CDK4 CCND1 | Palbociclib (CDK4/6) | Â | |
Basal-like 1 | Cell cycle | POLR1D POLD4 CDC25A CDCA7 BIRC3 WEE1 | ZM447439 (AURKA/B) PHA-793887 (CDK2/5/7) | Vinblastine (Microtubules) MLN8237 ((AURKA) BI-2536 (PLK1/2/3) Bortezomib (Proteasome) |
DNA repair | ATR HMCES LIG3 | KU-559333 (ATM) NU7441 (DNAPK) | BMN-673 (PARP1) Gemcitabine (DNA replication) Camptothecin (TOP1) | |
Basal-like 2 | DNA repair | RAD50 TERF1 | Olaparib (PARP) CP466722 (ATM) | Carboplatin (DNA akyl) Temozolomide (DNA akyl) Cyclophosphamide (DNA akyl) |
Developmental pathways | WNT3 JAG1 NODAL BMPR1A RSPO2 SMAD9 | Â | Â | |
MAPK signalling | MAP3K1 MAP2K4 | Trametinib (MEK1/2) PD0325901 (MEK1/2) Refametinib (MEK1/2) Slumetinib (MEK1/2) | Â | |
Mesenchymal | Adhesion/motility | RAC1 ITGAV RSPO1 CD44 ITGB3 | SL0101 (RSK) | TGFβRI inhibitor (SB-505124) JNK Inhibitor VIII (JNK) EHT 1864 (Rac GTPases) BIRB 0796 (p38/JNK2) |
Growth factor | FGFR1 FRS2 NGFR | Ponatinib (RTK) Midostaurin (kinase) BX796 (kinase) | Axitinib (multi − RTK) | |
Retinoic acid receptor alpha | RARA | Tretinoin (RARA agonist) | Â | |
Global hypomethylation and increased PRC2 activity Hypermethylation of immune response and antigen presentation promoter regions | Tazemetostat (EZH2 inhibitor) CPI-1205 (EZH2 inhibitor) MAK-683 (EED inhibitor) | Tazemetostat (EZH2 inhibitor) CPI-1205 (EZH2 inhibitor) MAK-683 (EED inhibitor) | ||