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

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 cM et was differentially regulated in isogenic pairs of epithelial and mesenchymal cell lines. Plk1 inhibition inhibits cM et phosphorylation only in mesenchymal cells. Constitutively active cM et abrogates Plk1 inhibitor–induced apoptosis. Likewise, cM et silencing or inhibition enhances Plk1 inhibitor–induced apoptosis. Cells with acquired resistance to Plk1 inhibitors are more epithelial than their parental cells and maintain cM et 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 cM et 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 cM et phosphorylation via β1‐integrin. This research defines a heretofore unknown mechanism of ligand‐independent activation of cM et downstream of Plk1 and an effective combination therapy.

Vimentin regulates Notch signaling strength and arterial remodeling in response to hemodynamic stress

“…Association of vimentin with signaling proteins has been shown to be regulated by vimentin phosphorylation and vimentin assembly state 48,49 . Shear stress did not significantly affect vimentin assembly state (Supplementary Fig.…”

Vimentin Intermediate Filaments as Potential Target for Cancer Treatment

“…The Plk1 inhibitor volasertib is a drug that induces apoptosis and also inhibits migration. Plk1 inhibition leads to a decrease in vimentin Ser82 phosphorylation and the corresponding loss of cMet phosphorylation via β1-integrin [118].…”

<p>Polo-like kinase 1 inhibition in NSCLC: mechanism of action and emerging predictive biomarkers</p>

“…This could also be shown in two erlotinib-resistant cell lines with activating EGFR mutations that harbored an EMT gene profile 49. Of note, it was recently shown that NSCLC cell lines (HEK293) with epithelial gene signature and constitutive cMET activation were highly resistant to volasertib treatment, whereas PLK1 inhibition prevented cMET phosphorylation in mesenchymal isogeneic cell pairs leading to high apoptosis rates.110 The combination of cMET and PLK1 inhibition in this setting led to sustainable xenograft tumor regression possibly paving the way for combination strategies involving PLK1 and cMET targeting therapy. Conclusively, acquired resistance to target therapies or conventional cytotoxic agents involving EMT might be a domain of PLK1 inhibition in the future.…”