Synthetic lethal interaction of combined BCL-XL and MEK inhibition promotes tumor regressions in KRAS mutant cancer models.
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.
Duke Scholars
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Related Subject Headings
- bcl-X Protein
- Sulfonamides
- Proto-Oncogene Proteins p21(ras)
- Oncology & Carcinogenesis
- Neoplasms
- Mice
- MAP Kinase Kinase Kinases
- Humans
- Drug Screening Assays, Antitumor
- Benzimidazoles
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- bcl-X Protein
- Sulfonamides
- Proto-Oncogene Proteins p21(ras)
- Oncology & Carcinogenesis
- Neoplasms
- Mice
- MAP Kinase Kinase Kinases
- Humans
- Drug Screening Assays, Antitumor
- Benzimidazoles