Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress
Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2011
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| Online Access: | http://hdl.handle.net/1721.1/67456 https://orcid.org/0000-0001-5785-8911 |
| _version_ | 1826215135392301056 |
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| author | Shaw, Alice Winslow, Monte Meier Magendantz, Margaret Ouyang, Chensi Dowdle, James Subramanian, Aravind Lewis, Timothy A. Maglathin, Rebecca L. Tolliday, Nicola Jacks, Tyler E |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Shaw, Alice Winslow, Monte Meier Magendantz, Margaret Ouyang, Chensi Dowdle, James Subramanian, Aravind Lewis, Timothy A. Maglathin, Rebecca L. Tolliday, Nicola Jacks, Tyler E |
| author_sort | Shaw, Alice |
| collection | MIT |
| description | Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-rasG12D allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras–expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras–driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies. |
| first_indexed | 2024-09-23T16:17:07Z |
| format | Article |
| id | mit-1721.1/67456 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:17:07Z |
| publishDate | 2011 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/674562022-09-29T19:21:31Z Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress Shaw, Alice Winslow, Monte Meier Magendantz, Margaret Ouyang, Chensi Dowdle, James Subramanian, Aravind Lewis, Timothy A. Maglathin, Rebecca L. Tolliday, Nicola Jacks, Tyler E Massachusetts Institute of Technology. Department of Biology Koch Institute for Integrative Cancer Research at MIT Jacks, Tyler E. Jacks, Tyler E. Shaw, Alice Winslow, Monte Meier Magendantz, Margaret Ouyang, Chensi Dowdle, James Activating K-RAS mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream signaling pathways have been shown to be deregulated by oncogenic K-ras. However, to date there are still no effective targeted therapies for this genetically defined subset of patients. Here we report the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts derived from a mouse model harboring a conditional oncogenic K-rasG12D allele. Among the >50,000 compounds screened, we identified a class of drugs with selective activity against oncogenic K-ras–expressing cells. The most potent member of this class, lanperisone, acts by inducing nonapoptotic cell death in a cell cycle- and translation-independent manner. The mechanism of cell killing involves the induction of reactive oxygen species that are inefficiently scavenged in K-ras mutant cells, leading to oxidative stress and cell death. In mice, treatment with lanperisone suppresses the growth of K-ras–driven tumors without overt toxicity. Our findings establish the specific antitumor activity of lanperisone and reveal oxidative stress pathways as potential targets in Ras-mediated malignancies. National Institutes of Health (U.S.) ((NIH) Grant 5K08CA111634-5) National Institutes of Health (U.S.) (grant 5-U01-CA84306) National Cancer Institute (U.S.) (Initiative for Chemical Genetics, NIH, under Contract N01-CO-12400) 2011-12-06T16:59:26Z 2011-12-06T16:59:26Z 2011-05 2011-04 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/67456 Shaw, A. T. et al. “Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress.” Proceedings of the National Academy of Sciences 108.21 (2011): 8773-8778. ©2011 by the National Academy of Sciences. https://orcid.org/0000-0001-5785-8911 en_US http://dx.doi.org/10.1073/pnas.1105941108 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Shaw, Alice Winslow, Monte Meier Magendantz, Margaret Ouyang, Chensi Dowdle, James Subramanian, Aravind Lewis, Timothy A. Maglathin, Rebecca L. Tolliday, Nicola Jacks, Tyler E Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title | Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title_full | Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title_fullStr | Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title_full_unstemmed | Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title_short | Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress |
| title_sort | selective killing of k ras mutant cancer cells by novel small molecule inducers of oxidative stress |
| url | http://hdl.handle.net/1721.1/67456 https://orcid.org/0000-0001-5785-8911 |
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