Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets

Abstract

Although hepatocellular carcinoma (HCC) is one of the deadliest health burdens worldwide, few drugs are available for its clinical treatment. However, in recent years, major breakthroughs have been made in the development of new drugs due to intensive fundamental research and numerous clinical trials in HCC. Traditional systemic therapy schemes and emerging immunotherapy strategies have both advanced. Between 2017 and 2020, the United States Food and Drug Administration (FDA) approved a variety of drugs for the treatment of HCC, including multikinase inhibitors (regorafenib, lenvatinib, cabozantinib, and ramucirumab), immune checkpoint inhibitors (nivolumab and pembrolizumab), and bevacizumab combined with atezolizumab. Currently, there are more than 1000 ongoing clinical trials involving HCC, which represents a vibrant atmosphere in the HCC drug research and development field. Additionally, traditional Chinese medicine approaches are being gradually optimized. This review summarizes FDA-approved agents for HCC, elucidates promising agents evaluated in clinical phase I/II/III trials and identifies emerging targets for HCC treatment. In addition, we introduce the development of HCC drugs in China. Finally, we discuss potential problems in HCC drug therapy and possible future solutions and indicate future directions for the development of drugs for HCC treatment.

Keywords: Immunotherapy; Liver cancer; Molecular mechanism; Traditional Chinese medicine; Treatment.

Fig. 1

Comprehensive and integrated multiomics analysis of hepatocellular carcinoma (HCC). The main signaling pathways and molecular events in HCC revealed by multiomics are shown. Each mutated gene is marked with an orange font for activation, a blue font for inactivation, and a black font for unclassified

Fig. 2

The timeline of FDA-approved drugs for hepatocellular carcinoma (HCC). Abbreviations: OS, overall survival; ORR, objective response rate; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand 1; CTLA-4, cytotoxic T lymphocyte-associated antigen-4

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