Abstract #2344: Selective killing of K-ras mutant cancer cells by novel, small molecule inducers of oxidative stress

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO 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 present the results of a small molecule, synthetic lethal screen using mouse embryonic fibroblasts (MEFs) derived from the conditional mouse strain LSL-K-rasG12D. In this strain, mutational activation of K-ras is regulated by a removable transcriptional silencing element. Among the 50,000 compounds screened, we have identified one class of drugs with selective activity against oncogenic K-ras-expressing cells. The most potent member of this class - lanperisone - demonstrates a 10-fold selectivity for K-ras mutant versus wildtype cells. Cell culture experiments show that 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 (ROS) which 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. These results establish the antitumor activity of lanperisone and reveal oxidative stress pathways as key targets in Ras-mediated malignancies. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2344.