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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Enhanced YAP expression leads to EGFR TKI resistance in lung adenocarcinomas

Ting-Fang Lee1, Yu-Chi Tseng2, Phung Anh Nguyen3,4

  • 1Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.

Scientific Reports
|January 12, 2018
PubMed

Insights

Yes-associated protein (YAP) drives resistance to EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma. Inhibiting YAP can re-sensitize resistant cells and potentially delay resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) mutations are key drivers in lung adenocarcinoma, with EGFR tyrosine kinase inhibitors (TKIs) offering targeted therapy.
  • Acquired resistance to TKIs and subsequent tumor recurrence remain significant challenges in treating EGFR-mutant lung adenocarcinoma.
  • Yes-associated protein (YAP) is implicated in promoting cancer progression, including proliferation, epithelial-mesenchymal transition, and drug resistance.

Purpose of the Study:

  • To investigate the role of YAP in the development and maintenance of TKI resistance in lung adenocarcinoma.
  • To evaluate the therapeutic potential of YAP inhibition, alone or in combination with EGFR TKIs, for overcoming TKI resistance.

Main Methods:

  • Assessed YAP expression and activation in TKI-sensitive and TKI-resistant lung adenocarcinoma cell lines.
  • Utilized shRNA and YAP inhibitors to reduce YAP expression and activity in resistant cells.
  • Evaluated the effect of YAP inhibition on TKI sensitivity in vitro and in xenograft models.
  • Analyzed patient survival data from the Taiwan National Health Insurance Research database for combined EGFR TKI and YAP inhibitor (statin) therapy.

Main Results:

  • Enhanced YAP expression was found to induce TKI resistance in sensitive lung adenocarcinoma cells.
  • Upregulated YAP expression and activation were observed in cells that developed long-term TKI resistance.
  • Reducing YAP expression or inhibiting its activity restored sensitivity to TKIs in resistant cells.
  • Combined EGFR TKI and YAP inhibition (statin) significantly reduced tumor size in xenografts and prolonged patient survival.

Conclusions:

  • YAP plays a critical role in promoting resistance to EGFR TKIs in lung adenocarcinoma.
  • Targeting YAP, in combination with EGFR TKIs, represents a promising therapeutic strategy to overcome TKI resistance and improve patient outcomes.
  • YAP inhibition may be a valuable approach to delay the onset of TKI resistance in lung adenocarcinoma patients.

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