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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Aniline Compounds / pharmacology
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Aniline Compounds / therapeutic use*
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Cell Line, Tumor
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Humans
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Mice
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Mice, Mutant Strains
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Mice, Nude
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Morpholines / pharmacology
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Morpholines / therapeutic use*
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Multiprotein Complexes / antagonists & inhibitors*
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Mutation
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Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins p21(ras)
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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bcl-X Protein / antagonists & inhibitors
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ras Proteins / genetics
Substances
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Aniline Compounds
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Antineoplastic Agents
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BCL2L1 protein, human
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KRAS protein, human
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MCL1 protein, human
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Morpholines
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Multiprotein Complexes
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Myeloid Cell Leukemia Sequence 1 Protein
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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bcl-X Protein
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(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
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BRAF protein, human
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Mechanistic Target of Rapamycin Complex 1
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins B-raf
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TOR Serine-Threonine Kinases
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Proto-Oncogene Proteins p21(ras)
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ras Proteins
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navitoclax