Non‐canonical cMet regulation by vimentin mediates Plk1 inhibitor–induced apoptosis

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. Synopsis In mesenchymal lung cancer, polo‐like kinase 1 (Plk1) inhibition leads to apoptosis owing to its direct effects on Plk1 and parallel vimentin and integrin‐mediated inhibition of cMet. Combining Plk1 and cMET inhibition shows therapeutic potentials in four mouse models of lung cancer. Plk1 inhibitor resistance correlates with cMet and epithelial protein expression in a large, independent dataset of non‐small cell lung cancer (NSCLC) cell lines. cMet phosphorylation is differentially regulated after Plk1 inhibition in resistant/epithelial and sensitive/mesenchymal NSCLC cell lines. Sustained cMet activation following Plk1 inhibition is a mechanism of both de novo and acquired resistance to Plk1 inhibitor‐induced apoptosis. The combination of cMet and Plk1 inhibition led to significant tumor regression in four independent NSCLC in vivo models treated with clinically relevant drugs. In mesenchymal NSCLC cells, cMet phosphorylation is regulated by Plk1‐mediated vimentin phosphorylation via β1‐integrin through a heretofore unknown mechanism of ligand‐independent cMet activation. Graphical Abstract In mesenchymal lung cancer, polo‐like kinase 1 (Plk1) inhibition leads to apoptosis owing to its