Abstract 875: Marked in vivo efficacy of combined BCLXL and MEK inhibition in KRAS mutant cancers revealed by a pooled shRNA-drug screen for genes that are “synthetically lethal” with MEK inhibitors

Abstract

Abstract Although KRAS is the most commonly mutated oncogene in human cancer, no effective therapies exist for KRAS mutant cancers. Attempts to target KRAS directly or to target single effector pathways downstream of KRAS have met limited success. Previously, our laboratory and others showed that simultaneous targeting of more than one KRAS effector pathway, specifically the MEK-ERK and PI3K-AKT pathways, can cause dramatic responses in KRAS-driven genetically-engineered mouse tumor models. These findings support the promise of targeted therapy combinations for KRAS mutant cancers and have led to clinical trials evaluating combined PI3K/MEK inhibition. We evaluated the efficacy of combined PI3K/MEK inhibition in a panel of 30 KRAS mutant cell lines. Roughly half of all cell lines showed limited sensitivity to this combination, suggesting that combined PI3K/MEK inhibition may only be effective in a subset of KRAS mutant cancers and underscoring the need for additional combination therapy strategies. To develop new targeted therapy combinations for KRAS mutant cancers, we designed a pooled shRNA-drug screen strategy aimed at rapidly identifying genes that, when inhibited, synergize with MEK inhibitors to decrease the viability of KRAS mutant cancer cells. Using this approach, we identified the anti-apoptotic protein BCLXL as a potential target for combination therapy with MEK inhibitors. When tested in vitro against a panel of 30 KRAS mutant cell lines, simultaneous pharmacologic inhibition of BCLXL (using the BH3 mimetic ABT-263) and MEK led to pronounced apoptosis and reduced viability in most cell lines, including many cell lines that were insensitive to combined PI3K/MEK inhibition. In vivo, the combination of ABT-263 and a MEK inhibitor led to marked tumor regressions in KRAS mutant xenograft models and to dramatic and sustained tumor regressions (>70% reduction in tumor size) in a KRAS-driven genetically-engineered mouse model of lung cancer. These findings suggest that combined inhibition of BCLXL and MEK is a promising targeted therapy combination for potential evaluation in clinical trials for patients with KRAS mutant cancers. 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 875. doi:1538-7445.AM2012-875