H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma

Abstract

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. .

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

“…Although multiple pan‐FGFR tyrosine inhibitors have already been evaluated in clinical trials for patients with abnormal FGFR signaling, their toxicity because of their low specificity has limited their use . Recently, selective FGFR4 inhibitors for the treatment of HCC were developed that overcame the shortcomings of pan‐FGFR inhibitors . One of the selective FGFR4 inhibitors, BLU9931, was reported to show remarkable antitumor ability in HCC harboring FGF19 amplification or in HCC overexpressing FGF19 that lacked amplification .…”

Analysis of Liver Cancer Cell Lines Identifies Agents With Likely Efficacy Against Hepatocellular Carcinoma and Markers of Response

“…FGF19 amplification is a very appealing therapeutic target with the development of selective inhibitors of its receptor, FGFR4. 30,31 However, FGF19 amplifications were not always associated with its overexpression both in LCCL and HCC tumors. We showed that only LCCL expressing a hepatocyte differentiation program with conserved expression of the FXR transcription factor and of the receptor complex, including FGFR4 and KLB, were sensitive to the FGFR4 inhibitors, which extends other previous findings.…”

Blocking FGFR4 exerts distinct anti‐tumorigenic effects in esophageal squamous cell carcinoma

“…H3B-6527 is a highly selective and covalent small-molecule inhibitor of FGFR4, which has been reported to be effective in inhibiting cell proliferation in vitro and in xenografts models of hepatocellular carcinoma. 22 Our results indicate that blocking FGFR4 by H3B-6527 could significantly inhibit ESCC cell proliferation in vitro. In additional, we found that FGFR4 blockade attenuated the migration and invasion ability of ESCC cells.…”

“…To explore the effects and mechanisms of blocking FGFR4 in ESCC, we selected two cell lines, KYSE150 and KYSE450, with relatively high FGFR4 expression levels for further study. H3B‐6527 is a highly selective and covalent small‐molecule inhibitor of FGFR4, which has been reported to be effective in inhibiting cell proliferation in vitro and in xenografts models of hepatocellular carcinoma . Our results indicate that blocking FGFR4 by H3B‐6527 could significantly inhibit ESCC cell proliferation in vitro.…”

“…Few studies have investigated whether FGFR4 protein expression is involved in pathogenesis and progression in ESCC. In this study, we selected a covalent inhibitor, H3B‐6527, which targets the unique hinge cysteine in the FGFR4 kinase domain that specifically inhibits FGFR4, and largely spares other FGFRs to play a blocking role . Thus, we explored the function of FGFR4 in the malignant growth of ESCC and investigated whether FGFR4 aberrations could serve as predictive biomarkers and potential therapeutic targets.…”