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Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models

2012; Cell Press; Volume: 23; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2012.11.007

1878-3686

Ryan B. Corcoran, Katherine A. Cheng, Aaron N. Hata, Anthony C. Faber, Hiromichi Ebi, Erin M. Coffee, Patricia Greninger, Ronald D. Brown, Jason Godfrey, Travis J. Cohoon, Youngchul Song, Eugene Lifshits, Kenneth E. Hung, Toshi Shioda, Dora Dias‐Santagata, Anurag Singh, Jeffrey Settleman, Cyril H. Benes, Mari Mino–Kenudson, Kwok‐Kin Wong, Jeffrey A. Engelman,

Melanoma and MAPK Pathways

Summary KRAS is the most commonly mutated oncogene, yet no effective targeted therapies exist for KRAS mutant cancers. We developed a pooled shRNA-drug screen strategy to identify genes that, when inhibited, cooperate with MEK inhibitors to effectively treat 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 many KRAS mutant cell lines from different tissue types. This combination caused marked in vivo tumor regressions in KRAS mutant xenografts and in a genetically engineered KRAS-driven lung cancer mouse model, supporting combined BCL-XL/MEK inhibition as a potential therapeutic approach for KRAS mutant cancers.