Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress |
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Authors: | Shaw Alice T Winslow Monte M Magendantz Margaret Ouyang Chensi Dowdle James Subramanian Aravind Lewis Timothy A Maglathin Rebecca L Tolliday Nicola Jacks Tyler |
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Institution: | aKoch Institute for Integrative Cancer Research,;bDepartment of Biology, and;eHoward Hughes Medical Institute, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139;;cMassachusetts General Hospital Cancer Center Home Cancer Center and Harvard Medical School, Boston, MA 02114; and;dBroad Institute of MIT and Harvard, Cambridge, MA 02142 |
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Abstract: | 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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Keywords: | targeted therapy synthetic lethality |
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