title: mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1.
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.
authors.affiliation: 1Massachusetts 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.
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.forename: Carlotta
authors.initials: C
authors.lastname: Costa
authors.forename: Anahita
authors.initials: A
authors.lastname: Dastur
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.forename: Alan T
authors.initials: AT
authors.lastname: Yeo
authors.forename: Elena J
authors.initials: EJ
authors.lastname: Edelman
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Ah Ting
authors.initials: AT
authors.lastname: Tam
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Boisvert
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Milano
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.forename: David P
authors.initials: DP
authors.lastname: Kodack
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Jain
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051020:bcl-X Protein / Q000037:antagonists & inhibitors; D018631:ras Proteins / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; C117307:KRAS protein, human; C579095:MCL1 protein, human; D009025:Morpholines; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C482119:BRAF protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; C528561:navitoclax