Abstract 3933: Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling

Abstract

Abstract Although targeted anticancer agents often result in dramatic responses, tumors invariably become resistant to these agents. A detailed understanding of the mechanisms by which tumors acquire resistance to such inhibitors should speed the development of more durable treatment strategies. The promise of RAF inhibition in metastatic melanoma is exemplary in this regard. Mutations in the BRAF oncogene have been detected in more than 50% of metastatic melanomas, and inhibition of mutant BRAF has shown high response rates in early clinical trials of patients with melanoma. However, resistance to RAF inhibition invariably develops. Mechanisms of de novo and acquired resistance to RAF inhibition remain poorly understood. Moreover, the clinical application of genomic approaches that might be capable of diagnosing salient resistance mechanisms remains underdeveloped. Here, we describe an approach to characterize genetic mechanisms of resistance through systematic tumor mutation profiling. We performed massively parallel sequencing of 138 cancer genes in a tumor specimen from a melanoma patient who developed resistance to PLX4032 after a dramatic initial response. The resulting profile identified a novel mutation in the downstream kinase MEK1 that was absent in the corresponding pre-treatment tumor. This MEK1 mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro. Our results provide an instructive framework both for assessing mechanisms of acquired resistance to kinase inhibition and deploying new technologies for elaboration of resistance mechanisms in a manner that may accelerate personalized cancer medicine. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3933. doi:10.1158/1538-7445.AM2011-3933