Data from Epithelial–Mesenchymal Transition Predicts Polo-Like Kinase 1 Inhibitor–Mediated Apoptosis in Non–Small Cell Lung Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> To identify new therapeutic targets for non–small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development.</p><p><b>Experimental Design:</b> To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor–induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines.</p><p><b>Results:</b> The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G<sub>2</sub>–M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial–mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (<i>P</i> < 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (<i>P</i> < 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, <i>KRAS</i> mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC.</p><p><b>Conclusions:</b> In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies. <i>Clin Cancer Res; 22(7); 1674–86. ©2015 AACR</i>.</p></div>