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Senesce to Survive: YAP-Mediated Dormancy Escapes EGFR/MEK Inhibition

Igor Bado1, Xiang H-F Zhang2

  • 1Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.

Cancer Cell
|January 18, 2020
PubMed

Insights

Lung cancer cells can survive EGFR and MEK inhibition by entering a senescence-like state. This survival is driven by the YAP/TEAD pathway, which reprograms cells to resist apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Therapeutic resistance remains a significant hurdle in effective cancer treatment.
  • Dual inhibition of Epidermal Growth Factor Receptor (EGFR) and Mitogen-activated protein kinase kinase (MEK) is a strategy used in lung cancer therapy.

Purpose of the Study:

  • To investigate the mechanisms by which lung cancer cells survive dual EGFR and MEK inhibition.
  • To identify key molecular pathways involved in therapeutic resistance.

Main Methods:

  • Utilized a senescence-like state model in lung cancer cells.
  • Investigated the role of the YAP/TEAD pathway.
  • Analyzed epigenomic reprogramming and epithelial-mesenchymal transition (EMT).

Main Results:

  • Lung cancer cells were observed to enter a senescence-like state, enabling survival under combined EGFR and MEK inhibition.
  • The YAP/TEAD pathway was identified as the mediator of this survival mechanism.
  • This pathway induced epigenomic reprogramming and EMT, counteracting apoptosis.

Conclusions:

  • A senescence-like state, mediated by the YAP/TEAD pathway, is a key mechanism of resistance to dual EGFR and MEK inhibition in lung cancer.
  • Targeting the YAP/TEAD pathway or its downstream effects could offer new therapeutic strategies to overcome resistance.

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