| Literature DB >> 29247039 |
Jaya Julie Joshi1, Heather Coffey1, Erik Corcoran1, Jennifer Tsai1, Chia-Ling Huang1, Kana Ichikawa1, Sudeep Prajapati1, Ming-Hong Hao1, Suzanna Bailey1, Jeremy Wu1, Victoria Rimkunas1, Craig Karr1, Vanitha Subramanian1, Pavan Kumar1, Crystal MacKenzie1, Raelene Hurley1, Takashi Satoh1, Kun Yu1, Eunice Park1, Nathalie Rioux1, Amy Kim1, Weidong G Lai2, Lihua Yu1, Ping Zhu1, Silvia Buonamici1, Nicholas Larsen1, Peter Fekkes1, John Wang1, Markus Warmuth1, Dominic J Reynolds1, Peter G Smith3, Anand Selvaraj3.
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. ©2017 American Association for Cancer Research.Entities:
Mesh：
Substances：
Year: 2017 PMID： 29247039 DOI： 10.1158/0008-5472.CAN-17-1865
Source DB: PubMed Journal: Cancer Res ISSN： 0008-5472 Impact factor: 12.701