Abstract 689: Characterization of two novel oncogenic FGFR2 fusions sensitive to the FGFR-selective inhibitor Debio 1347 in cholangiocarcinoma

Abstract

Abstract Dysregulation of the fibroblast growth factor receptor (FGFR) signaling pathway due to receptor overexpression, gene amplification, point mutations or fusions/chromosomal translocations is associated with cancer development and progression. FGFR gene fusions have recently been discovered in several indications including bladder cancer, glioblastoma, lung squamous cell cancer and cholangiocarcinoma. Predominant gene fusions have been identified in some indications such as FGFR3-TACC3 (with different genomic variations in the two genes) for bladder cancer whereas for other indications the genomic-altered landscape is a lot more heterogeneous, as seen in cholangiocarcinoma where at least ten FGFR2 fusions each with a different fusion partner have been identified. We herein report for the first time the discovery of two novel FGFR fusions in intra hepatic cholangiocarcinoma patient samples. These new fusions contain an intact FGFR2 tyrosine kinase domain and fused partner harbor oligomerization domains that suggest similar mechanism of constitutive kinase activation. Both fusions display oncogenic activities when introduced into Rat 2 cells in in vitro colony formation assays as compared to parental cells. The two fusions are also tumorigenic in vivo when implanted subcutaneously in NMRI nude mice, whereas parental cell do not grow in vivo. FGFR inhibition by the FGFR selective inhibitor Debio 1347 (CH5183284) reduced cell proliferation in vitro. In vivo sensitivity to FGFR inhibition could also be demonstrated for the two fusions. Altogether, these results suggest that these two novel oncogenic fusions are actionable targets in cholangiocarcinoma and that patients harboring these fusions could benefit from targeted FGFR inhibition, such as Debio 1347, currently investigated in a Phase I trial in selected patients harboring FGFR genetic alterations (NCT01948297). Citation Format: Anne Vaslin, Stefania Rigotti, Nathalie Lembrez, Grégoire Vuagniaux, Corinne Moulon, Hiroaki Tanaka. Characterization of two novel oncogenic FGFR2 fusions sensitive to the FGFR-selective inhibitor Debio 1347 in cholangiocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 689. doi:10.1158/1538-7445.AM2015-689