The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress
Open accessAbstract
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-ras G12D 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.
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Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity
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RAS–RAF–MEK-dependent oxidative cell death involving voltage-dependent anion channels
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A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene
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Self-citationSprouty-2 regulates oncogenic K-ras in lung development and tumorigenesis
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Metadata
- Authors
- Shaw, A. T., Winslow, M. M., Magendantz, M., Ouyang, C., Dowdle, J., Subramanian, A., Lewis, T. A., Maglathin, R. L., Tolliday, N., & Jacks, T.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2011-05-09
- Volume
- 108
- Issue
- 21
- Pages
- 8773-8778
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2096294661
- Cited by
- 230
- References
- 11
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- green
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- Shaw, A. T., Winslow, M. M., Magendantz, M., Ouyang, C., Dowdle, J., Subramanian, A., Lewis, T. A., Maglathin, R. L., Tolliday, N., & Jacks, T. (2011). Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1105941108
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