Inhibition of PLK1 Destabilizes EGFR and Sensitizes EGFR-Mutated Lung Cancer Cells to Small Molecule Inhibitor Osimertinib

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Abstract

Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) have significantly prolonged survival in EGFR-mutant non-small cell lung cancer patients. However, the development of resistance mechanisms prohibits the curative potential of EGFR TKIs. Combination therapies emerge as a valuable approach to preventing or delaying disease progression. Here, we investigated the combined inhibition of polo-like kinase 1 (PLK1) and EGFR in TKI-sensitive EGFR-mutant NSCLC cells. The pharmacological inhibition of PLK1 destabilized EGFR levels and sensitized NSCLC cells to Osimertinib through induction of apoptosis. In addition, we found that c-Cbl, a ubiquitin ligase of EGFR, is a direct phosphorylation target of PLK1 and PLK1 impacts the stability of c-Cbl in a kinase-dependent manner. In conclusion, we describe a novel interaction between mutant EGFR and PLK1 that may be exploited in the clinic. Co-targeting PLK1 and EGFR may improve and prolong the clinical response to EGFR TKI in patients with an EGFR-mutated NSCLC.

Original languageEnglish
Article number2589
JournalCancers
Volume15
Issue number9
DOIs
Publication statusPublished - May 2023

Bibliographical note

Funding Information:
This work was funded by Cancer Plan 29–39 Belgium (J.D.G.); the Wetenschappelijk Fonds Willy Gepts of the UZ Brussel, Belgium (P.G., J.D.G.); the UZ Brussel Foundation (P.G.); the Interdisciplinary Research Program (IRP) for Excellence on Cancer Research (S.B. & I.R., J.D.G. & G.J.G.); the FWO (G0C7514N grant) (G.J.G.); the BELSPO Interuniversity Attraction Poles (IAP-P7-07) (G.J.G.); the VUB (starting ZAP credit) (G.J.G.); and Innoviris (BB2B program) (G.J.G.). C.E. and P.G. were Ph.D. fellows of the FWO.

Publisher Copyright:
© 2023 by the authors.

Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.

Keywords

  • EGFR
  • Osimertinib
  • PLK1
  • Volasertib
  • c-Cbl
  • non-small cell lung cancer

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