title: Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress.
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.
authors.affiliation: Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
authors.forename: Margaret
authors.initials: M
authors.lastname: Magendantz
authors.forename: Chensi
authors.initials: C
authors.lastname: Ouyang
authors.forename: James
authors.initials: J
authors.lastname: Dowdle
authors.forename: Aravind
authors.initials: A
authors.lastname: Subramanian
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Lewis
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Maglathin
authors.forename: Nicola
authors.initials: N
authors.lastname: Tolliday
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000166:cytology; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000819:agonists; D018631:ras Proteins
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D018631:ras Proteins