Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (21), p.8773-8778
• Main 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
• Format: Article
• Language: English
• Subjects: alleles; Animal models; Animals; antineoplastic activity; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Biological Sciences; Cancer; Cell cycle; Cell death; Cell Death - drug effects; Cell lines; Cells, Cultured; Drug Evaluation, Preclinical; Drugs; Embryo fibroblasts; fibroblasts; Fibroblasts - cytology; humans; K-Ras protein; Killing; Malignancy; Mice; Molecular modelling; Molecules; mutants; Mutation; neoplasm cells; neoplasms; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidative stress; Oxidative Stress - drug effects; patients; ras Proteins; Reactive oxygen species; Reactive Oxygen Species - agonists; Rodents; Signal transduction; Toxicity; Translation; Tumors; Viability
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1105941108

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.