mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1.
Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that targets the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells. This specific susceptibility results from TORC1/2 inhibition leading to suppression of MCL-1 expression in mutant, but not WT, colorectal cancers, leading to abrogation of BIM/MCL-1 complexes. This combination strategy leads to tumor regressions in both KRAS-mutant colorectal cancer xenograft and genetically engineered mouse models of colorectal cancer, but not in the corresponding KRAS-WT colorectal cancer models. These data suggest that the combination of BCL-2/BCL-XL inhibitors with TORC1/2 inhibitors constitutes a promising targeted therapy strategy to treat these recalcitrant cancers.
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- ras Proteins
- bcl-X Protein
- TOR Serine-Threonine Kinases
- Sulfonamides
- Proto-Oncogene Proteins p21(ras)
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins B-raf
- Proto-Oncogene Proteins
- Protein Kinase Inhibitors
- Myeloid Cell Leukemia Sequence 1 Protein
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- ras Proteins
- bcl-X Protein
- TOR Serine-Threonine Kinases
- Sulfonamides
- Proto-Oncogene Proteins p21(ras)
- Proto-Oncogene Proteins c-bcl-2
- Proto-Oncogene Proteins B-raf
- Proto-Oncogene Proteins
- Protein Kinase Inhibitors
- Myeloid Cell Leukemia Sequence 1 Protein