Abstract 5593: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers

Abstract

Abstract ALK fusion oncogenes represent a novel molecular target in a small subset of non-small cell lung cancers (NSCLC). The vast majority of patients with ALK-positive NSCLC are highly responsive to ALK tyrosine kinase inhibitor (TKI) therapy. However, these patients invariably relapse, typically within one year, due to the development of resistance. Herein, we report findings from the first series of patients with acquired resistance to the ALK TKI crizotinib. In approximately one-third of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain. We also identified aberrant activation of other kinases as alternative mechanisms of crizotinib resistance. Additionally, we generated laboratory models of acquired crizotinib resistance which closely recapitulate the diversity of resistance mechanisms observed in patients. Our results highlight the marked heterogeneity of TKI resistance mechanisms in ALK-positive NSCLC, and provide the rationale for pursuing combinatorial therapeutic strategies in patients who relapse on crizotinib. 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 5593. doi:1538-7445.AM2012-5593