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Cancer Discov. 2014 May;4(5):554-63. doi: 10.1158/2159-8290.CD-13-0929. Epub 2014 Mar 14.

A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity.

Author information

  • 11Whitehead 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.

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.

PMID:
24631838
[PubMed - indexed for MEDLINE]
PMCID:
PMC4012430
Free PMC Article
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