Fig. 3
The main signaling pathways and molecular targets of targeted therapy for hepatocellular carcinoma (HCC). We summarize several crucial and well-established signaling pathways that drive HCC initiation and progression, as well as the core functional molecules and their partial regulators in these signaling cascades, and then list their targeted agents currently in clinical studies. Abbreviations: MST1/2, macrophage stimulating 1 and 2; SAV, salvador family WW domain containing protein; LATS1/2, large tumor suppressor kinases 1 and 2; MOB1A/B, MOB kinase activators 1A and B; YAP, yes-associated protein 1; NF2, neurofibromin 2; STK11, serine/threonine kinase 11; TEAD, TEA domain transcription factor; WWTR1/TAZ, WW domain containing transcription regulator 1; FGF19, fibroblast growth factor 19; FGFR4, fibroblast growth factor receptor 4; HSPG, heparin sulphate proteoglycans; FRS2/3, fibroblast growth factor receptor substrate 2 and 3; PLCγ, phospholipase C gamma 1; Fzd, frizzled; LRP, low-density lipoprotein receptor-related protein; DVL, dishevelled; APC, adenomatous polyposis coli; GSK3β, glycogen synthase kinase 3β; CK1α, casein kinase 1α; Smad3, mothers against decapentaplegic homolog 3; Rac1, Rac family small GTPase 1; TCF/LEF, T-cell factor/lymphoid enhancer factor; PI3K, phosphoinositide 3-kinase; PTEN, phosphatase and tensin homologue; TSC1/2, tuberous sclerosis 1/2; mTORC1/2, mammalian target of rapamycin complex 1/2; RHEB, RAS homologue enriched in brain; S6K, S6 kinase; AKT1S1, Akt1 substrate 1; 4EBP1/2, eukaryotic translation-initiation factor 4E-binding protein 1/2; MAPK, mitogen-activated protein kinase; SOS, SOS Ras/Rac guanine nucleotide exchange factor; GRB2, growth factor receptor bound-2; MEK1/2, mitogen-activated protein kinase kinase 1/2; ERK1/2, extracellular signal-regulated kinase 1/2; JAKs, janus kinases; STATs, signal transducers and activators of transcription; SOCS, suppressors of cytokine signaling; PTP, protein tyrosine phosphatase; PIAS, protein inhibitors of activated STAT; EGFR, epidermal growth factor receptor; TGF-α, transforming growth factor α; HGF, hepatocyte growth factor; CDC42, cell division cycle 42; ADAM10/TACE, tumor necrosis factor–converting enzyme; NICD, notch intracellular domain; RBP-Jκ, DNA-binding recombination signal-binding protein Jκ; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; TGF-βR1, transforming growth factor beta receptor 1; CDK4/6, cyclin dependent kinase 4/6; SK2, sphingosine kinase 2; DNMT, DNA methyltransferase; IDH1, isocitrate dehydrogenase (NADP(+)) 1; Smo, smoothened, frizzled class receptor; A3AR, adenosine A3 receptor; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte–associated antigen-4; LAG-3, lymphocyte activating 3; Tim-3, T-Cell immunoglobulin and mucin domain-containing molecule 3