Abstract 3858: Gains in FGF19 are predictive of response to the fibroblast growth factor receptor (FGFR) small molecule tyrosine kinase inhibitor BGJ 398 in vitro

Abstract

Abstract Background: Hepatocellular carcinoma (HCC) is a leading cause of cancer death world-wide. Sorafenib, a multi-targeted small molecule inhibitor of the vascular endothelial growth factor (VEGF) receptor and other kinases is the only approved systemic agent in advanced HCC. Despite multiple studies defining the molecular heterogeneity of HCC, clinical trials of new agents do not pre-select for predictive markers. The fibroblast growth factor (FGF) receptor consists of 4 receptor tyrosine kinases and over 20 ligands. Differential expression and activation of these receptors and ligands have been implicated in oncogenesis and the pathogenesis of HCC (Sawey 2011). BGJ398 is a selective small molecule tyrosine kinase inhibitor of the FGFR family of receptors 1-4. Given the molecular diversity of HCC, we hypothesized that there would be a subset of HCC that would be more dependent on FGFR inhibition and used cell line models to identify predictive markers of response to BGK 398. Methods: 20 human HCC cell lines were used. In vitro dose response curves were generated using direct cell count assays over 6 days. IC 50 values were calculated from the dose response curves. Genomic data on the cell lines was derived using the Agilent 105K CGH platform. These data were analyzed in the context of the sensitivity data to BGJ 398. Western blot analysis was performed for effects of BGJ398 on phospho-FRS2Δ (tyr-196), a downstream signaling molecule for FGFR activation. Flow cytometry was performed for effects of BGJ 398 on the cell cycle and apoptosis. Results: There was differential sensitivity to BGJ 398 across the HCC cell lines. 3 cell lines were identified as having IC 50 values less than 1 μM versus the remaining cell lines which were all >1 uM. When analyzed in the context of the CGH data, all 3 cell lines had gains in FGF 19 of log2 ratio of 0.9 to 2.6. BGJ inhibited FRS2α activation in all cell lines tested. Flow cytometry revealed the BGJ induced cell cycle arrest in sensitive lines without significant apoptosis. Conclusions: Gains in FGF19 are predictive for growth inhibitory effects of BGJ398 in human HCC cell lines in vitro and provide rationale for patient selection in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3858. doi:1538-7445.AM2012-3858