Abstract 3667: Inactivating BRAF mutations confer dasatinib sensitivity in lung cancer

Abstract

Abstract NSCLC is a lethal disease for which personalized therapies that target specific genetic aberrations have been markedly effective in subsets of patients. An important approach for discovering effective cancer therapeutic targets is to characterize responsive tumors. We conducted a phase II trial of the tyrosine kinase inhibitor dasatinib in stage IV NSCLC. The dramatic response of one patient, who remains cancer free four years later, led us to examine the molecular characteristics of his tumor. We performed a comprehensive analysis of this NSCLC patient's tumor including mutational analysis of 40 genes, array comparative genomic hybridization, and immunohistochemistry. We discovered a novel, inactivating BRAF mutation (Y472CBRAF) in the patient's tumor; no inactivating BRAF mutations were found in the non-responding patients. Cells transfected with Y472CBRAF exhibited CRAF, MEK, and ERK activation, which were identical to signaling changes that occur with previously known inactivating BRAF mutants. Dasatinib induced senescence in NSCLC cells with endogenous inactivating BRAF mutations. Transfection of cells with inactivating BRAF mutations led to increased dasatinib sensitivity; conversely, cells transfected with an activating BRAF mutation were more resistant. Likewise, BRAF inhibition in NSCLC cells expressing wild-type BRAF enhanced dasatinib sensitivity. Dasatinib sensitivity may depend upon CRAF since dasatinib led to decreased CRAF activity and only NSCLC cells with inactivating BRAF mutations were sensitive to CRAF inhibition. We hypothesize that patient's BRAF mutation was likely responsible for his marked response to dasatinib and suggests that tumors bearing inactive BRAF mutations will be exquisitely sensitive to dasatinib. 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 3667. doi:1538-7445.AM2012-3667