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

  • Cancer Res. 2017 Dec 15;77(24):6999-7013. doi: 10.1158/0008-5472.CAN-17-1865.
Jaya Julie Joshi  1 ,  Heather Coffey  1 ,  Erik Corcoran  1 ,  Jennifer Tsai  1 ,  Chia-Ling Huang  1 ,  Kana Ichikawa  1 ,  Sudeep Prajapati  1 ,  Ming-Hong Hao  1 ,  Suzanna Bailey  1 ,  Jeremy Wu  1 ,  Victoria Rimkunas  1 ,  Craig Karr  1 ,  Vanitha Subramanian  1 ,  Pavan Kumar  1 ,  Crystal MacKenzie  1 ,  Raelene Hurley  1 ,  Takashi Satoh  1 ,  Kun Yu  1 ,  Eunice Park  1 ,  Nathalie Rioux  1 ,  Amy Kim  1 ,  Weidong G Lai  2 ,  Lihua Yu  1 ,  Ping Zhu  1 ,  Silvia Buonamici  1 ,  Nicholas Larsen  1 ,  Peter Fekkes  1 ,  John Wang  1 ,  Markus Warmuth  1 ,  Dominic J Reynolds  1 ,  Peter G Smith  3 ,  Anand Selvaraj  3
Affiliations
PMID: 29247039 DOI: 10.1158/0008-5472.CAN-17-1865
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. Cancer Res; 77(24); 6999-7013. ©2017 AACR.

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