Abstract 4408: Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention

Abstract

Abstract Non-small cell lung cancer (NSCLC) is the most frequent lung cancer subtype and it affects near 1.5 million patients worldwide annually. The lack of actionable mutations in NSCLC patients presents a significant hurdle in the administration of targeted therapies for this disease, and their identification is an urgent unmet need. Here we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cancer cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we show that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies. Citation Format: PEDRO Torres-Ayuso, Ewelina Testoni, Natalie L. Stephenson, Anna A. Marusiak, Eleanor W. Trotter, Andrew Hudson, Cassandra L. Hodgkinson, Christopher J. Morrow, Caroline Dive, John Brognard. Mutant ABL1 is a genetic dependency in non-small cell lung cancer amenable to pharmacological intervention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4408.