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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1105941108

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

Publication TypeJournal Article
Year of Publication2011
AuthorsShaw, AT, Winslow, MM, Magendantz, M, Ouyang, C, Dowdle, J, Subramanian, A, Lewis, TA, Maglathin, RL, Tolliday, N, Jacks, T
JournalProc Natl Acad Sci U S A
Volume108
Issue21
Pages8773-8
Date Published2011 May 24
ISSN1091-6490
KeywordsAnimals, Antineoplastic Agents, Cell Death, Cells, Cultured, Drug Evaluation, Preclinical, Fibroblasts, Mice, Neoplasms, Oxidative Stress, ras Proteins, Reactive Oxygen Species
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.

DOI10.1073/pnas.1105941108
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21555567?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21555567
PubMed Central IDPMC3102385
Grant List5K08CA111634-5 / CA / NCI NIH HHS / United States
U01 CA084306 / CA / NCI NIH HHS / United States
K08 CA111634 / CA / NCI NIH HHS / United States
5-U01-CA84306 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States