Journal
CANCER CELL
Volume 23, Issue 1, Pages 121-128Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.11.007
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Funding
- NIH [P50 CA127003, P50CA090578, R01CA140594, 1U54HG006097-01, R01CA122794, R01CA163896]
- American Cancer Society Institutional Research grant
- Damon Runyon Clinical Investigator award
- Conquer Cancer Foundation of ASCO Young Investigator award
- V Foundation [K08CA120060, R01CA137008, 1U01CA41457-01]
- American Cancer Society [RSG-06-102-01-CCE]
- Ellison Foundation Scholar
- AstraZeneca
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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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