Abstract 1302: A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse gastric cancer

Abstract Dysregulation of fibroblast growth factor receptors (FGFRs) signaling has been associated with tumorigenesis and progression in various cancers. Preclinical models have shown that FGFR2 signaling activation due to FGFR2 amplification is essential driver for specific gastric cancers. Cancer cell lines or patient-derived gastric cancer xenograft models with FGFR2 amplification are highly sensitive to AZD4547, which is a small-molecule tyrosine kinase (TRK) inhibitor that selectively targets FGFR1-3. However, recent clinical trial studies failed to demonstrate the therapeutic potential of AZD4547 in patients with FGFR2 amplification. For this study, we identified critical genetic and molecular features that determine the response to FGFR2 inhibitors in gastric cancer. To systematically delineate the pathways that modulate response to FGFR2 inhibitors, we identified CRISPR-library-based gene knockouts that result in resistance to AZD4547 in Kato III cells, a gastric cancer cell line with high sensitivity to this drug. Although majority of transduced Kato III cells undergo cell senescence upon AZD4547 treatment, a small population of resistant cells rendered by CRISPR knockout is enriched. Subsequent sequencing and pathway analysis reveal the alternative activated pathways that contribute to the cell growth in lieu of FGFR2 inhibition. Furthermore, we applied the elastic-net regression analysis to identify genetic features associated with the drug sensitivity to FGFR2 inhibition in cancer cell lines. The cell line drug response data are derived from the Cancer Therapeutic Response Portal (CTRP v2) and the Cancer Cell Line Encyclopedia (CCLE). Notably, few cancer cell lines have high FGFR2 copy numbers (CN>4). The elastic-net algorithm simultaneously integrates mutation, copy number, gene expression data, and forms multiple linear regression to learn the coefficient weights associated with FGFR2 inhibitor sensitivity. Using the method, we identify the whole spectrum of genetic and molecular features that are potential drug response markers. In summary, our study provides new insight into genetic and molecular features that implicate in the cellular response to FGFR2 inhibitors, which can facilitate the development of more effective strategies to treat patients with FGFR2 amplification. Citation Format: Jiamin Chen, Hojoon Lee, Hanlee Ji. A comprehensive approach to delineate FGFR2 targeted therapy response in diffuse gastric cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1302.