H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma
| Autor: | Suzanna L. Bailey, Pete Smith, Victoria Rimkunas, Raelene Hurley, Kun Yu, Lihua Yu, Craig Karr, Ping Zhu, Markus Warmuth, Reynolds Dominic, Takashi Satoh, Anand Selvaraj, Silvia Buonamici, Jennifer Tsai, Erik Corcoran, Jaya Julie Joshi, Crystal MacKenzie, Chia-Ling Huang, Nicholas A. Larsen, Weidong G. Lai, Nathalie Rioux, Amy Kim, Eunice Park, Pavan Kumar, Peter Fekkes, V. Subramanian, Sudeep Prajapati, John Q. Wang, Kana Ichikawa, Heather Coffey, Jeremy Wu, Ming-Hong Hao |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Carcinoma Hepatocellular Mice Nude Antineoplastic Agents Palbociclib Heterocyclic Compounds 4 or More Rings Mice 03 medical and health sciences Cell Line Tumor medicine Carcinoma Animals Humans Receptor Fibroblast Growth Factor Type 4 Receptor Mice Inbred BALB C business.industry Liver Neoplasms Cancer FGF19 Fibroblast growth factor receptor 4 medicine.disease Xenograft Model Antitumor Assays digestive system diseases Fibroblast Growth Factors Cell Transformation Neoplastic 030104 developmental biology Oncology Fibroblast growth factor receptor Hepatocellular carcinoma Cancer research Female business |
| Zdroj: | Cancer Research. 77:6999-7013 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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