Abstract 291: ERK1/2 pathway activation controls epithelial-mesenchymal transition in NSCLC cells.

Abstract

Abstract Understanding and overcoming the cellular mechanisms that underlie de novo and acquired therapy resistance remains a challenge in treating many cancers including non-small cell lung cancer (NSCLC). Despite the prevalence of epidermal growth factor receptor (EGFR) over-activation in NSCLC and other cancers, most patients are resistant to EGFR inhibitors. A number of studies have linked mesenchymal cellular phenotypes and epithelial-mesenchymal transition (EMT) with resistance to chemotherapeutics and EGFR inhibitors across cancer types. Here, we demonstrate in NSCLC cells that MAPK/ERK signaling plays a key role in determining mesenchymal cellular characteristics and response to the EGFR inhibitor gefitinib. In cultured NSCLC cell lines, pharmacological inhibition of MEK pushed cells toward a more epithelial phenotype and prevented EMT induction by exogenous transforming growth factor beta. In addition, chronic MEK inhibition synergistically enhanced cellular sensitivity to gefitinib in a reversible manner and slowed cell migration in wound healing assays in NSCLC cell lines with both de novo and acquired resistance to gefitinib. Importantly, our results demonstrate that the observed cell phenotypic changes occur on a time scale corresponding to that with which epithelial and mesenchymal marker expression change in response to ERK inhibition. This time scale is much larger than that for changes in ERK activity itself, reflecting the need for downstream ERK-dependent processes to affect phenotypic changes. Changes in the same cellular phenotypes and associated changes in epithelial and mesenchymal markers also occurred as a result of KRAS mutant expression in a MEK-dependent manner. Overall, this study draws a strong connection between ERK pathway activation and mesenchymal characteristics in NSCLC and suggests potential new opportunities for expanding the efficacy of currently available EGFR inhibitors. Citation Format: Janine M. Buonato, Matthew J. Lazzara. ERK1/2 pathway activation controls epithelial-mesenchymal transition in NSCLC cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 291. doi:10.1158/1538-7445.AM2013-291