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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. 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. 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 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. We also identified miR-10a inhibitor as increasing cell viability, with the converse observed for miR-10a mimic, suggesting that miR-10a acts as a tumor suppressor gene by directly decreasing expression of gene(s) that promote cell survival and growth. Manipulation of miR-10a levels also resulted in significant changes in both mRNA and protein levels of its predicted target, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which has been shown to play a major role in proliferation and survival in a number of human cancers and is a significant therapeutic target. We have identified miR-337-3p as a regulator of taxane sensitivity, and miR-10a and miR-139-5p as modulators of cell viability. Increasing levels of miR-337-3p and inhibiting miR-10a and miR-139-5p may therefore provide novel therapeutic tools for the treatment of NSCLC and SCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 140. doi:1538-7445.AM2012-140

We are addressing the questions of whether microRNAs (miRNAs) play a functional role in modulating drug sensitivity of lung cancer cells, and whether miRNA expression levels can be manipulated to increase drug sensitivity in lung cancer treatment. Using a combination of in silico and in vitro approaches, we identified miR-337-3p as a modulator of paclitaxel sensitivity in NSCLC cell lines where over-expression of miR-337-3p sensitizes NSCLC NCI-H1155 cells to paclitaxel (>2 fold) and docetaxel (>10 fold) by enhancing taxane-induced mitotic arrest. Of several possible targets of miR-337-3p we found that Stat3 and Rap1A are the direct targets responsible for mediating miR-337-3p sensitization to paclitaxel. In studies of multiple NSCLC lines we found that miR-337-3p can, in general, sensitize NSCLC lines to paclitaxel, and that Stat3 expression is significantly correlated with paclitaxel resistance in NSCLC lines, suggesting that tumor Stat3 expression is an intrinsic determinant and biomarker for paclitaxel response. We conclude we have discovered a novel pathway modulating NSCLC paclitaxel sensitivity, which involves the down-regulation of Stat3 and Rap1A expression by miR-337-3p. These findings have prompted: our ongoing studies of patient samples annotated for miR-337-3p, Stat3, and Rap1A expression and response to taxane therapy; preclinical testing of a miR-337-3p mimic as an adjuvant to taxanes for NSCLC therapy; and further tests of this pathway to provide both new therapeutic targets and biomarkers predictive of response for NSCLC taxane based therapy. 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 4709. doi:10.1158/1538-7445.AM2011-4709