Abstract 2163: Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC

There are currently no effective targeted therapeutic strategies for KRAS mutant non-small cell lung cancer (NSCLC). Single agent MEK inhibitors have demonstrated showed disappointing clinical activity, partly due to inability to induce a robust apoptotic response. Combining MEK inhibitors with BCL-XL/BCL-2 inhibitors may be effective for a subset of KRAS mutant cancers that are dependent on BCL-XL for survival, however this combination is unlikely to be an effective strategy for cancers dependent on MCL-1. We investigated the effect of combining the MEK inhibitor trametinib with a novel MCL-1 inhibitor (compound A), which possesses potent and selective anti-MCL-1 activity in vitro and in vivo, on KRAS mutant cancers. In contrast to colorectal cancer models, which are largely sensitive to combined MEK + BCL-XL inhibition, a subset of cell line and patient-derived mouse xenograft (PDX) KRAS mutant NSCLC models were significantly more sensitive to MEK + MCL-1 inhibition compared to MEK + BCL-XL. To model potential clinical strategies, we tested intermittent dosing regimens and unexpectedly discovered a method strategy for dramatically sensitizing KRAS mutant NSCLC cells to the MEK + MCL-1 combination. These studies provide rationale for the clinical evaluation of combined MEK + MCL-1 inhibitors for KRAS mutant NSCLC. Citation Format: Aaron N. Hata, Faria M. Siddiqui, Maria Gomez-Caraballo, Samantha J. Bilton, Daria Timonina, Varuna Nangia, Angela Coxon, Sean Caenepeel, Paul Hughes. Combined targeting of MEK and MCL-1 induces apoptosis and tumor regression of KRAS mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2163. doi:10.1158/1538-7445.AM2017-2163