Selective Killing of K-ras Mutant Cancer Cells by Novel Small Molecule Inducers of Oxidative Stress
Author(s)
Shaw, Alice; Winslow, Monte Meier; Magendantz, Margaret; Ouyang, Chensi; Dowdle, James; Subramanian, Aravind; Lewis, Timothy A.; Maglathin, Rebecca L.; Tolliday, Nicola; Jacks, Tyler E; ... Show more Show less
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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.
Date issued
2011-05Department
Massachusetts Institute of Technology. Department of Biology; Koch Institute for Integrative Cancer Research at MITJournal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
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.
Version: Final published version
ISSN
0027-8424
1091-6490