Abstract B7: microRNA regulation of cell viability and drug sensitivity in lung cancer

Abstract

Abstract Introduction: Lung cancer is the leading cause of cancer-related deaths, with the majority of deaths due to failed therapy from tumor drug resistance. Third-generation chemotherapeutic agents represent the standard first-line treatment for advanced small cell (SCLC) and non-small cell (NSCLC) lung cancer patients. Response rates are poor (20–40%) with a median survival of 8–10 months. Methods: In an unbiased and comprehensive approach, we have combined a high-throughput screening platform with a library of chemically synthesized microRNA mimics and inhibitors. We have used this platform to identify mimics and inhibitors that reduce cell viability in general, and those that specifically sensitize cells to taxanes. Results: We have identified several miRNAs for which over-expression or inhibition has a dramatic and selective effect on cell viability or drug response. We have demonstrated that miR-337-3p mimic sensitizes NSCLC cells to taxanes. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p by enhancing taxane-induced arrest in the G2 phase of the cell cycle. We have also identified an inhibitor of miR-139-5p as a potent and selective regulator of SCLC cell viability. Inhibiting miR-139-5p decreases SCLC cell viability by over 80%, but has a minimal cytotoxic effect on that of NSCLCs or immortalized human bronchial epithelial cells. We are currently investigating the targets of miR-139-5p that mediate its effect on SCLC cell viability. Conclusion: We have identified miR-337-3p as a regulator of taxane sensitivity in NSCLC, and miR-139-5p as a modulator of viability in SCLC. Increasing levels of miR-337-3p and inhibiting miR-139-5p may therefore provide novel therapeutic tools for the treatment of NSCLC and SCLC lung tumors, respectively. Citation Format: Liqin Du, Christopher DeSevo, Borkowski Robert, Baker Michael, Adi F. Gazdar, John D. Minna, Alexander Pertsemlidis. microRNA regulation of cell viability and drug sensitivity in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B7.