RRC ID 67469
Author Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T.
Title First Selective Small Molecule Inhibitor of FGFR4 for the Treatment of Hepatocellular Carcinomas with an Activated FGFR4 Signaling Pathway.
Journal Cancer Discov
Abstract UNLABELLED:Aberrant signaling through the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR 4) signaling complex has been shown to cause hepatocellular carcinoma (HCC) in mice and has been implicated to play a similar role in humans. We have developed BLU9931, a potent and irreversible small-molecule inhibitor of FGFR4, as a targeted therapy to treat patients with HCC whose tumors have an activated FGFR4 signaling pathway. BLU9931 is exquisitely selective for FGFR4 versus other FGFR family members and all other kinases. BLU9931 shows remarkable antitumor activity in mice bearing an HCC tumor xenograft that overexpresses FGF19 due to amplification as well as a liver tumor xenograft that overexpresses FGF19 mRNA but lacks FGF19 amplification. Approximately one third of patients with HCC whose tumors express FGF19 together with FGFR4 and its coreceptor klotho β (KLB) could potentially respond to treatment with an FGFR4 inhibitor. These findings are the first demonstration of a therapeutic strategy that targets a subset of patients with HCC.
SIGNIFICANCE:This article documents the discovery of BLU9931, a novel irreversible kinase inhibitor that specifically targets FGFR4 while sparing all other FGFR paralogs and demonstrates exquisite kinome selectivity. BLU9931 is efficacious in tumors with an intact FGFR4 signaling pathway that includes FGF19, FGFR4, and KLB. BLU9931 is the first FGFR4-selective molecule for the treatment of patients with HCC with aberrant FGFR4 signaling.
Volume 5(4)
Pages 424-37
Published 2015-4-1
DOI 10.1158/2159-8290.CD-14-1029
PII 2159-8290.CD-14-1029
PMID 25776529
MeSH Amino Acid Sequence Animals Antineoplastic Agents / chemistry Antineoplastic Agents / pharmacology Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / metabolism* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Cell Proliferation / drug effects Disease Models, Animal Humans Liver Neoplasms / drug therapy Liver Neoplasms / metabolism* Liver Neoplasms / pathology Mice Models, Molecular Molecular Conformation Molecular Sequence Data Protein Binding Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology* Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors Receptor, Fibroblast Growth Factor, Type 4 / chemistry Receptor, Fibroblast Growth Factor, Type 4 / metabolism* Sequence Alignment Signal Transduction / drug effects* Xenograft Model Antitumor Assays
IF 29.497
Human and Animal Cells HuH-7