FGFR4 inhibitors for the treatment of hepatocellular carcinoma: a synopsis of therapeutic potential

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca Cancer J Clin. 2021;71:209–249.
   PubMed Web of Science ®Google Scholar
• Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16:589–604.
   PubMed Web of Science ®Google Scholar
• Ferrante N, Pillai A, Signal A. Update on the diagnosis and treatment of hepatocellular carcinoma. Curr Gastroenterol Rep. 2020;16:506–516.
   Google Scholar
• Tejeda-Maldonado J, García-Juárez I, Aguirre-Valadez J, et al. Diagnosis and treatment of hepatocellular carcinoma: an update. World J Hepatol. 2015;7:362–376.
   PubMed Web of Science ®Google Scholar
• Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. New Engl J Med. 2020;382:1894–1905.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. New Engl J Med. 2008;359:378–390.
   PubMed Web of Science ®Google Scholar
• Abou-Alfa GK, Meyer T, Cheng A-L, et al. Cabozantinib in patients with advanced and progressing hepatocellular carcinoma. New Engl J Med. 2018;379:54–63.
   PubMed Web of Science ®Google Scholar
• Kudo M, Finn RS, Qin S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet [Internet]. 2018;391:1163–1173.
   PubMed Web of Science ®Google Scholar
• El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet [Internet]. 2017;389:2492–2502.
   PubMed Web of Science ®Google Scholar
• Zhu AX, Kang YK, Yen CJ, et al. Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased $\alpha$-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol [Internet]. 2019;20:282–296.
   PubMed Web of Science ®Google Scholar
• Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
   PubMed Web of Science ®Google Scholar
• Xie Y, Su N, Yang J, et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther [Internet]. 2020;5:181.
   PubMed Web of Science ®Google Scholar
• Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10:116–129.
   PubMed Web of Science ®Google Scholar
• Szybowska P, Kostas M, Wesche J, et al. Cancer mutations in FGFR2 prevent a negative feedback loop mediated by the ERK1/2 pathway. Cells. 2019;8:500–518.
   Web of Science ®Google Scholar
• Sharpe R, Pearson A, Herrera-Abreu MT, et al. FGFR signaling promotes the growth of triple-negative and basal-like breast cancer cell lines both in vitro and in vivo. Clin Cancer Res. 2011;17:5275–5286.
   PubMed Web of Science ®Google Scholar
• Jomrich G, Hudec X, Harpain F, et al. Expression of FGF8, FGF18, and FGFR4 in gastroesophageal adenocarcinomas. Cells. 2019;8:1–13.
   Web of Science ®Google Scholar
• Kim RD, Sarker D, Meyer T, et al. First-in-human phase i study of fisogatinib (BLU-554) validates aberrant FGF19 signaling as a driver event in hepatocellular carcinoma. Cancer Discov. 2019;9:1696–1707.
   PubMed Web of Science ®Google Scholar
• Inagaki T, Dutchak P, Zhao G, et al. Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 2007;5:415–425.
   PubMed Web of Science ®Google Scholar
• Sawey ET, Chanrion M, Cai C, et al. Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell. 2011;19:347–358.
   PubMed Web of Science ®Google Scholar
• Schulze K, Imbeaud S, Letouzé E, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–511.
   PubMed Web of Science ®Google Scholar
• Totoki Y, Tatsuno K, Covington KR, et al. Trans-ancestry mutational landscape of hepatocellular carcinoma genomes. Nat Genet. 2014;46:1267–1273.
   PubMed Web of Science ®Google Scholar
• Repana D, Ross P. Targeting FGF19/FGFR4 pathway: a novel therapeutic strategy for hepatocellular carcinoma. Dis. 2015;3:294–305.
   Google Scholar
• Wang Y, Liu D, Zhang T, et al. FGF/FGFR signaling in hepatocellular carcinoma: from carcinogenesis to recent therapeutic intervention. Cancers (Basel). 2021;13:1360.
   PubMed Web of Science ®Google Scholar
• Drafahl KA, McAndrew CW, Meyer AN, et al. The receptor tyrosine kinase FGFR4 negatively regulates NF-kappaB signaling. Plos One. 2010;5:e14412.
   PubMed Web of Science ®Google Scholar
• Beenken A, Mohammadi M. Endocrine FGFs and Klothos (Springer: New York, NY); 2012; p. 1–24. Available from: http://link.springer.com/10.1007/978-1-4614-0887-1
   Google Scholar
• Huynh H, Lee LY, Goh KY, et al. Infigratinib mediates vascular normalization, impairs metastasis, and improves chemotherapy in hepatocellular carcinoma. Hepatology. 2019;69:943–958.
   PubMed Web of Science ®Google Scholar
• Liu Y, Cao M, Cai Y, et al. Dissecting the role of the FGF19-FGFR4 signaling pathway in cancer development and progression. Front Cell Dev Biol. 2020;8:95.
   PubMed Web of Science ®Google Scholar
• Desnoyers LR, Pai R, Ferrando RE, et al. Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene. 2008;27:85–97.
   PubMed Web of Science ®Google Scholar
• French DM, Lin BC, Wang M, et al. Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models. Plos One. 2012;7:1–12.
   Web of Science ®Google Scholar
• Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17:1–13.
   PubMed Web of Science ®Google Scholar
• Zhou M, Yang H, Learned RM, et al. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis. Nat Commun [Internet]. 2017;8:1–16. Available from: https://doi.org/http://dx.doi.org/10.1038/ncomms15433.
   PubMed Web of Science ®Google Scholar
• Kang HJ, Haq F, Sung CO, et al. Characterization of hepatocellular carcinoma patients with FGF19 amplification assessed by fluorescence in situ hybridization: a large cohort study. Liver Cancer. 2019;8:12–23.
   PubMed Web of Science ®Google Scholar
• Kir S, Kliewer SA, Mangelsdorf DJ. Roles of FGF19 in liver metabolism. Cold Spring Harbor Symp. 2011;76:139–144.
   PubMedGoogle Scholar
• Kurosu H, Choi M, Ogawa Y, et al. Tissue-specific expression of $\beta$klotho and Fibroblast Growth Factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem [Internet]. 2007;282:26687–26695.
   PubMed Web of Science ®Google Scholar
• Lee JJX, Choo SP. The fibroblast growth factor receptor pathway in hepatocellular carcinoma. Hepatoma Res. 2018;4:52.
   Google Scholar
• Liu WY, Xie DM, Zhu GQ, et al. Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target. Expert Opin Ther Tar. 2015;19:675–685.
   PubMed Web of Science ®Google Scholar
• Nicholes K, Guillet S, Tomlinson E, et al. A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol [Internet]. 2002;160:2295–2307. Available from: https://doi.org/http://dx.doi.org/10.1016/S0002-9440(10)61177-7
   PubMed Web of Science ®Google Scholar
• Touat M, Ileana E, Postel-Vinay S, et al. Targeting FGFR signaling in cancer. Clin Cancer Res. 2015;21:2684–2694.
   PubMed Web of Science ®Google Scholar
• Zhou SL, Zhou ZJ, Hu ZQ, et al. CXCR2/CXCL5 axis contributes to epithelial-mesenchymal transition of HCC cells through activating PI3K/Akt/GSK-3 USD\beta$/Snail signaling. Cancer Lett [Internet]. 2015;358:124–135.
   PubMed Web of Science ®Google Scholar
• Goetz R, Mohammadi M. Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol. 2013;14:166–180.
   PubMed Web of Science ®Google Scholar
• Zhao H, Lv F, Liang G, et al. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3 USD\beta$/$\beta$-catenin signaling cascade via FGFR4 activation. Oncotarget. 2016;7:13575–13586.
   PubMedGoogle Scholar
• Wu S, Ye S, Lin X, et al. Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling. Cancer Lett [Internet]. 2021;499:175–187.
   PubMed Web of Science ®Google Scholar
• Chen J, Du F, Dang Y, et al. Fibroblast growth factor 19–mediated up-regulation of SYR-related high-mobility group box 18 promotes hepatocellular carcinoma metastasis by transactivating fibroblast growth factor Receptor 4 and fms-related tyrosine Kinase 4. Hepatology. 2020;71:1712–1731.
   PubMed Web of Science ®Google Scholar
• Gao L, Wang X, Tang Y, et al. FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Canc Res [Internet]. 2017;36:1–10.
   PubMed Web of Science ®Google Scholar
• Lee KJ, Jang YO, Cha S-K, et al. Expression of fibroblast growth Factor 21 and β-Klotho regulates hepatic fibrosis through the nuclear factor-κB and c-Jun N-Terminal kinase pathways. Gut Liver. 2018;12:449–456.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Montal R, Sia D, et al. Molecular therapies and precision medicine for hepatocellular carcinoma. Nat Rev Clin Oncol [Internet]. 2018;15:599–616.
   PubMed Web of Science ®Google Scholar
• Granito A, Forgione A, Marinelli S, et al. Experience with regorafenib in the treatment of hepatocellular carcinoma. Therap Adv Gastroenterol. 2021;14:17562848211016959.
   Web of Science ®Google Scholar
• Kanzaki H, Chiba T, Ao J, et al. The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma. Sci Rep. 2021;11:5303.
   PubMed Web of Science ®Google Scholar
• Tucker JA, Klein T, Breed J, et al. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure [Internet]. 2014;22:1764–1774.
   PubMed Web of Science ®Google Scholar
• Krook MA, Reeser JW, Ernst G, et al. Fibroblast growth factor receptors in cancer: genetic alterations, diagnostics, therapeutic targets and mechanisms of resistance. Br J Cancer [Internet]. 2021;124:880–892.
   PubMed Web of Science ®Google Scholar
• Clinicaltrials.gov. Study to evaluate the safety, pharmacokinetics, and pharmacodynamics of JNJ-42756493 (Erdafitinib) in participants with advanced hepatocellular carcinoma [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02421185
   Google Scholar
• Lu X, Chen H, Patterson AV, et al. Fibroblast Growth Factor Receptor 4 (FGFR4) selective inhibitors as hepatocellular carcinoma therapy: advances and prospects. J Med Chem. 2019;62:2905–2915.
   PubMedGoogle Scholar
• Hagel M, Miduturu C, Sheets M, et al. First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov. 2015;5:424–437.
   PubMed Web of Science ®Google Scholar
• Joshi JJ, Coffey H, Corcoran E, et al. H3B-6527 Is a potent and selective inhibitor of FGFR4 in FGF19-Driven hepatocellular carcinoma. Cancer Res. 2017;77:6999–7013.
   PubMed Web of Science ®Google Scholar
• Weiss A, Adler F, Buhles A, et al. FGF401, A first-in-class highly selective and potent FGFR4 inhibitor for the treatment of FGF19-driven hepatocellular cancer. Mol Cancer Ther. 2019;18:2194–2206.
   PubMed Web of Science ®Google Scholar
• Huynh H, Prawira A, Le TBU, et al. FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma. Exp Mol Med. 2020;52:1857–1868.
   PubMed Web of Science ®Google Scholar
• Liu PCC, Lu L, Bowman K, et al. Abstract 2100: selective inhibition of FGFR4 by INCB062079 is efficacious in models of FGF19- and FGFR4-dependent cancers. Exp Mol Ther. 2017:2100.
   Google Scholar
• Ruggeri B, Stubbs M, Yang Y, et al. Abstract 1234: the novel FGFR4-selective inhibitor INCB062079 is efficacious in models of hepatocellular carcinoma harboring FGF19 amplification. Exp Mol Ther. 2017:1234.
   Google Scholar
• Bartz R, Fukuchi K, Ohtsuka T, et al. Preclinical development of U3-1784, a novel FGFR4 antibody against cancer, and avoidance of its on-target toxicity. Mol Cancer Ther. 2019;18:1832–1843.
   PubMed Web of Science ®Google Scholar
• ClinicalTrials.gov. A Phase 1 study of fisogatinib (BLU-554) in patients with hepatocellular carcinoma [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02508467
   Google Scholar
• Clinicaltrials.gov. A Phase Ib/II study of fisogatinib(BLU-554) in subjects with hepatocellular carcinoma [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT04194801
   Google Scholar
• ClinicalTrials.gov. An open-label safety and tolerability study of INCB062079 in subjects with advanced hepatocellular carcinoma and other malignancies [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT03144661
   Google Scholar
• ClinicalTrials.gov. Phase 1 study to evaluate the safety, pharmacokinetics and pharmacodynamics of H3B-6527 in participants with advanced hepatocellular carcinoma [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02834780
   Google Scholar
• Macarulla T, Moreno V, Chen L-T, et al. Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC). J Clin Oncol. 2021;39:4090.
   Web of Science ®Google Scholar
• Chan SL, Yen C-J, Schuler M, et al. Abstract CT106: ph I/II study of FGF401 in adult pts with HCC or solid tumors characterized by FGFR4/KLB expression. Clin Trials. 2017;CT106–CT106.
   Google Scholar
• ClinicalTrials.gov. FGF401 in HCC and Solid Tumors Characterized by Positive FGFR4 and KLB Expression [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/results/NCT02325739
   Google Scholar
• ClinicalTrials.gov. An open study assessing the safety and tolerability of U3-1784 [Internet]; n.d. [cited 2021 Oct 8]. Available from: https://clinicaltrials.gov/ct2/show/NCT02690350
   Google Scholar
• Ciprotti M, Abraham R, Jansen M, et al. A phase I, open label, two part, safety and tolerability study of U3-1784 in patients with advanced solid tumours. J Clin Oncol. 2016;34: TPS2593–TPS2593.
   Google Scholar
• Hatlen MA, Schmidt-Kittler O, Sherwin CA, et al. Acquired on-target clinical resistance validates fgfr4 as a driver of hepatocellular carcinoma. Cancer Discov. 2019;9:1686–1695.
   PubMed Web of Science ®Google Scholar
• Llovet JM, Hernandez-Gea V. Hepatocellular carcinoma: reasons for Phase III failure and novel perspectives on trial design. Clin Cancer Res. 2014;20:2072–2079.
   PubMed Web of Science ®Google Scholar
• Ally A, Balasundaram M, Carlsen R, et al. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–1341.e23.
   PubMed Web of Science ®Google Scholar
• Pal SK, Rosenberg JE, Hoffman-Censits JH, et al. Efficacy of BGJ398, a fibroblast growth factor receptor 1-3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 2018;8:CD-18-0229.
   PubMed Web of Science ®Google Scholar
• Farrell B, Breeze AL. Structure, activation and dysregulation of fibroblast growth factor receptor kinases: perspectives for clinical targeting. Biochem Soc Trans. 2018;46:1753–1770.
   PubMed Web of Science ®Google Scholar
• Lewin J, Siu LL. Development of fibroblast growth factor receptor inhibitors: kissing frogs to find a prince? J Clin Oncol. 2015;33:3372–3374.
   PubMed Web of Science ®Google Scholar
• Subbiah V, Pal SK. Precision oncology for hepatocellular cancer: slivering the liver by FGF19–FGFR4–KLB pathway inhibition. Cancer Discov. 2019;9:1646–1649.
   PubMed Web of Science ®Google Scholar
• Pai R, French D, Ma N, et al. Antibody-mediated inhibition of fibroblast growth Factor 19 results in increased bile acids synthesis and ileal malabsorption of bile acids in cynomolgus monkeys. Toxicol Sci. 2012;126:446–456.
   PubMed Web of Science ®Google Scholar
• Granito A, Muratori L, Lalanne C, et al. Hepatocellular carcinoma in viral and autoimmune liver diseases: role of CD4+ CD25+ Foxp3+ regulatory T cells in the immune microenvironment. World J Gastroenterol. 2021;27:2994–3009.
   PubMed Web of Science ®Google Scholar