Abstract C193: FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a novel orally bioavailable, selective, and potent FGFR inhibitor.

Abstract

Abstract The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTK) consists of FGFR1, FGFR2, FGFR3 and FGFR4, which are the high affinity receptors for 22 different FGF ligands. These ligand-receptor combinations elicit a broad spectrum of biological activities during development and in adult tissue homeostasis. In contrast, de-regulated FGF signaling has been linked to diseases, most prominently in the pathogenesis of multiple cancers. Epidemiological and molecular studies have revealed a variety of genetic alterations in components of the FGF/FGFR signaling system which result in aberrant receptor activation and thus, enhanced downstream signaling. Hence, on this basis, targeted inhibition of FGFRs can be exploited for therapeutic intervention. In this report we disclose NVP-BGJ398, a novel orally bioavailable, selective and potent kinase inhibitor of the FGFRs currently in Phase I clinical trials. We further describe the identification of patient stratification biomarkers for NVP-BGJ398 by intersecting genome-wide gene expression data with genomic alterations and cell line sensitivity data across an annotated collection of cancer cell lines termed “Cancer Cell Line Encyclopedia”. We show that genetic alterations for selected FGF/FGFR family members predict for sensitivity to NVP-BGJ398 in specific cancer types, thus providing the rationale for clinical trials in well defined subpopulations of cancer patients based upon the presence of these molecular abnormalities. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C193.