H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma.
Cancer Res
; 77(24): 6999-7013, 2017 12 15.
Article
in En
| MEDLINE
| ID: mdl-29247039
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.
Full text:
1
Database:
MEDLINE
Main subject:
Cell Transformation, Neoplastic
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Carcinoma, Hepatocellular
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Receptor, Fibroblast Growth Factor, Type 4
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Fibroblast Growth Factors
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Heterocyclic Compounds, 4 or More Rings
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Liver Neoplasms
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Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Animals
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Female
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Humans
Language:
En
Year:
2017
Type:
Article