Abstract 3958: A miRNA inhibitor screen for synthetic lethal interactions in KRAS-driven NSCLC

Abstract

Abstract Lung cancer, especially non-small cell lung cancer (NSCLC), is currently the leading cause of cancer fatalities in the United States, accounting for 30% of the fatalities in males, and 26% in females. Additionally, the five-year survival rate for individuals affected by lung cancer has only improved by 3% in the past 35 years. As suggested by the survival data, very few effective treatment options are available for NSCLC, and many vary dramatically in efficacy depending on the genetic status of the tumor. In particular, the presence of mutant KRAS in NSCLC serves as a negative predictor for drug efficacy. KRAS mutations are found in ∼22% of NSCLC tumors, and tumors harboring these mutations are especially refractory to treatment. We have identified synthetic lethal miRNAs in the background of KRAS-dependence through a four-armed miRNA inhibitor screen. A miRNA inhibitor screen can serve to not only identify miRNAs involved in context-dependent survival, but also genes and pathways that would be obscured by genomic redundancy in a conventional RNAi screen. Using a comprehensive library of miRNA inhibitors coupled with an endpoint assay for cell viability, we can identify miRNAs that modulate viability or paclitaxel sensitivity in KRAS-dependent NSCLC cell line NCI-H358 with minimal effect in the wild-type KRAS cell line NCI-H1993. Candidate miRNAs are validated in an expanded panel of ten cell lines including four KRAS mutant, four KRAS wild-type, and two immortalized human bronchial epithelial cell lines. The miRNAs identified here will allow us to elucidate vulnerable pathways in KRAS-dependent tumors that can be exploited for a therapeutic or predictive benefit in a typically difficult to manage class of tumor. This research was supported by NIH R01 CA129632 from the National Cancer Institute and by P50 CA70907 from the UT Southwestern/MD Anderson Cancer Center Lung Specialized Program of Research Excellence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3958. doi:10.1158/1538-7445.AM2011-3958