Abstract PR09: Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS-mutant cancer models

Although KRAS is the most commonly mutated oncogene in human cancer, KRAS has proven difficult to target pharmacologically, and no effective therapies exist for KRAS-mutant cancers. Recently, there has been evidence that targeted therapy combinations inhibiting multiple downstream effectors of KRAS may be a promising approach for KRAS-mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to kill KRAS-mutant cancer cells. The anti-apoptotic BH3 family gene BCL-XL emerged as a top hit through this approach. ABT-263 (navitoclax), a chemical inhibitor that blocks the ability of BCL-XL to bind and inhibit pro-apoptotic proteins, in combination with a MEK inhibitor led to dramatic apoptosis in the vast majority of KRAS-mutant cell lines tested from different tissue types. Mechanistic studies revealed that MEK inhibition led to marked induction of the pro-apoptotic protein BIM in KRAS-mutant cancer cells, but that BIM remained bound and inhibited by BCL-XL. Pharmacologic inhibition of BCL-XL with ABT-263 disrupted this inhibitory complex, allowing BIM to trigger apoptosis. Epithelial differentiation and E-cadherin expression correlated with increased sensitivity to this inhibitor combination across a panel of 30 KRAS-mutant cell lines, while epithelial-to-mesenchymal transition (EMT) correlated with resistance. This combination also caused marked in vivo tumor regressions in three independent KRAS-mutant xenografts and in established lung tumors in two genetically-engineered KRAS-driven lung cancer mouse models. These data support combined BCL-XL/MEK inhibition as a promising therapeutic approach for evaluation in future clinical trials for patients with KRAS-mutant cancers. This abstract is also presented as Poster B19. Citation Format: Ryan B. Corcoran, Katherine A. Cheng, Aaron N. Hata, Anthony C. Faber, Hiromichi Ebi, Erin M. Coffee, Patricia Greninger, Ronald D. Brown, Jason T. Godfrey, Travis J. Cohoon, Youngchul Song, Eugene Lifshits, Toshi Shioda, Dora Dias-Santagata, Anurag Singh, Jeffrey Settleman, Cyril H. Benes, Mari Mino-Kenudson, Kwok-Kin Wong, Jeffrey A. Engelman. Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS-mutant cancer models. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR09.