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Updated: Jan 25, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

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Non-canonical cMet regulation by vimentin mediates Plk1 inhibitor-induced apoptosis

Ratnakar Singh1, Shaohua Peng1, Pavitra Viswanath1,2

  • 1Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

EMBO Molecular Medicine
|May 2, 2019
PubMed

Insights

Polo-like kinase (Plk1) inhibitors show promise for non-small-cell lung cancer (NSCLC) therapy. Combining Plk1 inhibitors with cMet inhibitors effectively treats epithelial NSCLC by overcoming resistance mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Mesenchymal non-small-cell lung cancer (NSCLC) shows sensitivity to polo-like kinase (Plk1) inhibitors.
  • Mechanisms of resistance to Plk1 inhibitors in epithelial NSCLC are not well understood.
  • cMet signaling plays a role in NSCLC progression and therapeutic resistance.

Purpose of the Study:

  • To elucidate the mechanisms of resistance to Plk1 inhibitors in epithelial NSCLC.
  • To investigate the role of cMet in regulating sensitivity and resistance to Plk1 inhibitors.
  • To evaluate the efficacy of combined cMet and Plk1 inhibition as a therapeutic strategy for NSCLC.

Main Methods:

  • Utilized isogenic epithelial and mesenchymal NSCLC cell lines to study differential gene regulation.
  • Assessed the impact of Plk1 inhibition on cMet phosphorylation and downstream signaling.
  • Employed animal NSCLC models to evaluate the therapeutic potential of monotherapy and combination therapy.

Main Results:

  • Plk1 inhibition differentially affects cMet phosphorylation in mesenchymal versus epithelial cells.
  • Constitutively active cMet confers resistance to Plk1 inhibitor-induced apoptosis; cMet inhibition enhances sensitivity.
  • Combined cMet and Plk1 inhibition resulted in complete tumor regression without regrowth in preclinical models.

Conclusions:

  • Identified a novel mechanism of ligand-independent cMet activation downstream of Plk1.
  • Demonstrated that acquired resistance to Plk1 inhibitors is associated with epithelial phenotype and cMet activation.
  • Established a potent combination therapy of cMet and Plk1 inhibitors for treating resistant epithelial NSCLC.
Keywords:
NSCLCPlk1cMetdrug combinationvimentin

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