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Cancer Cell. 2013 Jan 14;23(1):121-8. doi: 10.1016/j.ccr.2012.11.007. Epub 2012 Dec 13.

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

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1
Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.

Abstract

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.

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PMID:
23245996
PMCID:
PMC3667614
DOI:
10.1016/j.ccr.2012.11.007
[Indexed for MEDLINE]
Free PMC Article

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