A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity
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...
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| Format: | Article |
| Language: | en_US |
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American Association for Cancer Research
2015
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| Online Access: | http://hdl.handle.net/1721.1/96742 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826214301867704320 |
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| author | Grabiner, Brian C. Nardi, Valentina Birsoy, Kivanc Possemato, Richard Shen, Kuang Sinha, Sumi Jordan, Alexander Beck, Andrew H. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Grabiner, Brian C. Nardi, Valentina Birsoy, Kivanc Possemato, Richard Shen, Kuang Sinha, Sumi Jordan, Alexander Beck, Andrew H. Sabatini, David |
| author_sort | Grabiner, Brian C. |
| collection | MIT |
| description | 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.
Significance: We report that a diverse set of cancer-associated MTOR mutations confer increased mTORC1/2 pathway activity and that cells harboring these mutations are highly sensitive to rapamycin in culture and in vivo. These findings are clinically relevant as the MTOR mutations characterized herein may serve as biomarkers for predicting tumor responses to mTOR inhibitors. |
| first_indexed | 2024-09-23T16:03:22Z |
| format | Article |
| id | mit-1721.1/96742 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:03:22Z |
| publishDate | 2015 |
| publisher | American Association for Cancer Research |
| record_format | dspace |
| spelling | mit-1721.1/967422022-09-29T17:53:26Z A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity Grabiner, Brian C. Nardi, Valentina Birsoy, Kivanc Possemato, Richard Shen, Kuang Sinha, Sumi Jordan, Alexander Beck, Andrew H. Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Sabatini, David M. 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. Significance: We report that a diverse set of cancer-associated MTOR mutations confer increased mTORC1/2 pathway activity and that cells harboring these mutations are highly sensitive to rapamycin in culture and in vivo. These findings are clinically relevant as the MTOR mutations characterized herein may serve as biomarkers for predicting tumor responses to mTOR inhibitors. Starr Cancer Consortium David H. Koch Institute for Integrative Cancer Research at MIT Alexander and Margaret Stewart Trust National Institutes of Health (U.S.) (Grant CA103866) National Institutes of Health (U.S.) (Grant CA129105) National Institutes of Health (U.S.) (Grant AI07389) 2015-04-23T17:15:49Z 2015-04-23T17:15:49Z 2014-03 2014-03 Article http://purl.org/eprint/type/JournalArticle 2159-8274 2159-8290 http://hdl.handle.net/1721.1/96742 Grabiner, B. C., V. Nardi, K. Birsoy, R. Possemato, K. Shen, S. Sinha, A. Jordan, A. H. Beck, and D. M. Sabatini. “A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity.” Cancer Discovery 4, no. 5 (March 14, 2014): 554–563. https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1158/2159-8290.cd-13-0929 Cancer Discovery Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research PMC |
| spellingShingle | Grabiner, Brian C. Nardi, Valentina Birsoy, Kivanc Possemato, Richard Shen, Kuang Sinha, Sumi Jordan, Alexander Beck, Andrew H. Sabatini, David A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title | A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title_full | A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title_fullStr | A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title_full_unstemmed | A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title_short | A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity |
| title_sort | diverse array of cancer associated mtor mutations are hyperactivating and can predict rapamycin sensitivity |
| url | http://hdl.handle.net/1721.1/96742 https://orcid.org/0000-0002-1446-7256 |
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