312 (PB092) - Mechanisms of resistance toward FGFR4 inhibition in hepatocellular carcinoma

Abstract

Background: Hepatocellular carcinoma (HCC), which accounts for up to 90% of all primary liver cancers, is a leading cause of cancer mortality worldwide. FGF19 is a gut secreted endocrine hormone that acts in liver through its unique receptor FGFR4 and co-receptor KLB, to regulate bile acid synthesis and hepatocyte proliferation. FGF19 is reported to be overexpressed and/or amplified in ∼30% of HCC. Genomic and functional studies have identified FGF19 as a potential driver oncogene in HCC. Several FGFR4 inhibitors have entered clinical trials for treating HCC patients. BLU-554 is a potent, selective, and irreversible FGFR4 inhibitor that has demonstrated preliminary efficacy as a second-line treatment in HCC patients harboring FGF19 overexpression. The observed responses, however, on average only last few months before patient relapse, suggesting likely occurrence of acquired resistance. Here, we investigated the changes that occur with long-term FGFR4 inhibition and the development of resistance in preclinical HCC models, in order to identify resistance mechanisms and possible combination strategies. Materials and methods: We established resistant cell lines following long-term exposure of Huh7 with BLU-554. Proteomic, genomic and transcriptomic characterizations were performed to identify potential resistance mechanisms. Results: Huh7 cells resistant to BLU-554 were generated and confirmed with insensitivity to BLU-554. In addition, the cells were also resistant to other FGFR4 inhibitors including FGF-401, H3B-6527 and erdafitinib. Genomic analysis found no mutations on the FGFR4 gene itself. Proteomic analysis revealed activation of a RTK in the BLU-554 resistant cells compared with the parental cells. Transcriptomic analysis revealed changes in gene expression and GSEA analysis revealed multiple relevant gene sets were significantly enriched in the resistant cells. We tested several inhibitors against the identified RTK pathway and found complete inhibition this pathway could restore BLU-554 sensitivity. Conclusions: These data suggest the bypass activation of other RTK may contribute to acquired resistance of FGFR4 inhibition and potential combination strategy to overcome resistance. No conflict of interest.