Abstract
To address the need for improved systemic therapy for non–small‐cell lung cancer (NSCLC), we previously demonstrated that mesenchymal NSCLC was sensitive to polo‐like kinase (Plk1) inhibitors, but the mechanisms of resistance in epithelial NSCLC remain unknown. Here, we show that cMet was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cMet phosphorylation only in mesenchymal cells. Constitutively active cMet abrogates Plk1 inhibitor–induced apoptosis. Likewise, cMet silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cMet activation after Plk1 inhibition. In four animal NSCLC models, mesenchymal tumors were more sensitive to Plk1 inhibition alone than were epithelial tumors. The combination of cMet and Plk1 inhibition led to regression of tumors that did not regrow when drug treatment was stopped. Plk1 inhibition did not affect HGF levels but did decrease vimentin phosphorylation, which regulates cMet phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cMet downstream of Plk1 and an effective combination therapy.
Highlights
Lung cancer remains the most lethal cancer, contributing to 27% of cancer-related deaths in the United States (Siegel et al, 2018)
Varying numbers of proteins were associated with sensitivity to four Polo-like kinase 1 (Plk1) inhibitors: 33 proteins were associated with sensitivity to BI2536, with sensitivity to GSK461364, with sensitivity to BRD-K70511574, and 26 with sensitivity to GW-843682X (Fig EV1A–D)
We found that cMet protein expression correlated with drug sensitivity for all Plk1 inhibitors (P < 0.01; Figs 1B and EV1E)
Summary
Lung cancer remains the most lethal cancer, contributing to 27% of cancer-related deaths in the United States (Siegel et al, 2018). Despite Plk1’s reputation as an essential protein for cell survival, Plk inhibitors are well tolerated by patients (Nokihara et al, 2016; Pujade-Lauraine et al, 2016; Schoffski et al, 2012, 2010; Sebastian et al, 2010; Stadler et al, 2014; Van den Bossche et al, 2016) and there are diverse biological responses to Plk inhibition or knockdown in cancer cells (Choi et al, 2015; Craig et al, 2014; Driscoll et al, 2014; Gjertsen & Schoffski, 2015; McCarroll et al, 2015; Medema et al, 2011; Rudolph et al, 2009; Spankuch-Schmitt et al, 2002). We previously compared gene mutation and basal gene and protein expression among 63 NSCLC cell lines and discovered that mesenchymal NSCLC cell lines were more sensitive to Plk inhibitors than were epithelial cell lines in vitro and in vivo; KRAS, TP53, and MET mutations did not consistently
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