title: A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity.
abstract: Genes encoding components of the PI3K-AKT-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR complex 1 (mTORC1) signaling in cells expressing various activating mutations remains sensitive to pharmacologic mTOR inhibition, but is partially resistant to nutrient deprivation. Finally, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.
authors.affiliation: 1Whitehead Institute for Biomedical Research; 2Howard Hughes Medical Institute and Department of Biology, MIT; 3Broad Institute of Harvard and MIT; 4The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge; 5Department of Pathology, Massachusetts General Hospital Cancer Center; and 6Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Grabiner
authors.forename: Valentina
authors.initials: V
authors.lastname: Nardi
authors.forename: Kıvanc
authors.initials: K
authors.lastname: Birsoy
authors.forename: Richard
authors.initials: R
authors.lastname: Possemato
authors.forename: Kuang
authors.initials: K
authors.lastname: Shen
authors.forename: Sumi
authors.initials: S
authors.lastname: Sinha
authors.forename: Alexander
authors.initials: A
authors.lastname: Jordan
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Beck
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016208:Databases, Factual; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009374:Neoplasms, Experimental; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus