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

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

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Mutant Strains
  • Mice, Nude
  • Morpholines / pharmacology
  • Morpholines / therapeutic use*
  • Multiprotein Complexes / antagonists & inhibitors*
  • Mutation
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins p21(ras)
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • bcl-X Protein / antagonists & inhibitors
  • ras Proteins / genetics

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • BCL2L1 protein, human
  • KRAS protein, human
  • MCL1 protein, human
  • Morpholines
  • Multiprotein Complexes
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • (5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol
  • BRAF protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins B-raf
  • TOR Serine-Threonine Kinases
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins
  • navitoclax