Abstract A106: Induction of synthetic lethality in mutant KRAS cells for lung cancer prevention and therapy

Abstract

Abstract Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low five-year survival rate despite improved treatment strategies. Mutations and activation of KRAS occur frequently in non-small cell lung cancers (NSCLCs) and are associated with higher risk of drug-resistance, tumor recurrence, and poor prognosis. Currently, there are no effective therapies for targeting mutant KRAS and there is a great need to develop such a strategy. We have previously discovered a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and mutant KRAS in premalignant lung epithelial cells, which allows for chemoprevention of KRAS-driven lung cancer by the combination of TRAIL and Smac mimic [Cancer Prev Res (Phila). 2011 May;4(5):666–73.]. Here we demonstrated that this synthetic lethal interaction also exists in malignant lung cancer cells. We showed that 3 out of 4 lung cancer cell lines harboring mutant KRAS displayed high sensitivity to the combination of TRAIL and Smac mimic and KRAS wild type lung cancer cell lines were resistant to the treatment. Expression of mutant KRAS in KRAS wild type lung cancer cells sensitized these cells to TRAIL and Smac mimic and knocking down of mutant KRAS in mutant KRAS expressing cells resulted in resistance to the treatment. Furthermore, we showed that TRAIL and Smac mimic treatment inhibited xenograft tumor growth in mutant KRAS dependent manner. Mechanistically, we found that mutant KRAS repressed cellular FADD-like interleukin 1β–converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through the activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Mutant KRAS also enhanced the secretion of Prostate Apoptosis Response-4 (Par4) to promote TRAIL-induced apoptosis. Our study provided a potential new approach for lung cancer chemoprevention and therapy based on synthetic lethality that targets mutant KRAS for apoptosis using the combination of and Smac mimic. Citation Information: Cancer Prev Res 2011;4(10 Suppl):A106.