Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress.
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.
|Year of Publication
Proc Natl Acad Sci U S A
2011 May 24
|PubMed Central ID
5K08CA111634-5 / 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