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Cancer Discov. 2014 Jan;4(1):42-52. doi: 10.1158/2159-8290.CD-13-0315. Epub 2013 Oct 25.

mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1.

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  • 11Massachusetts General Hospital Cancer Center; 2Department of Medicine, Harvard Medical School; 3Division of Gastroenterology, Department of Medicine, Tufts Medical Center; 4Department of Pathology, Massachusetts General Hospital, Boston; and 5Radiation Oncology, Steele Lab for Tumor Biology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.

Abstract

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.

[PubMed - indexed for MEDLINE]
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