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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly

Monique B Nilsson1, Huiying Sun1, Jacqulyne Robichaux1

  • 1Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Science Translational Medicine
|September 4, 2020
PubMed

Insights

Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is driven by the YAP/FOXM1 axis, promoting multidrug resistance. Targeting this axis and spindle assembly checkpoint (SAC) proteins offers new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a significant clinical challenge, particularly when driven by EGFR-independent mechanisms like epithelial-to-mesenchymal transition (EMT).
  • Understanding the molecular drivers of this resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To identify the molecular mechanisms underlying EGFR TKI resistance mediated by EMT.
  • To investigate the role of the yes-associated protein (YAP) and forkhead box protein M1 (FOXM1) axis in this resistance.
  • To explore potential therapeutic vulnerabilities associated with this resistance phenotype.

Main Methods:

  • Integrated transcriptomic, proteomic, and drug screening approaches were employed.
  • Analysis of spindle assembly checkpoint (SAC) protein abundance in resistant cells.
  • Evaluation of patient specimens from EGFR-mutant lung cancer.

Main Results:

  • Activation of the YAP/FOXM1 axis was identified as a driver of EMT-associated EGFR TKI resistance.
  • EGFR TKI resistance was linked to broad multidrug resistance and increased abundance of SAC proteins (PLK1, Aurora kinases, survivin, KSP).
  • EGFR TKI-resistant cells showed vulnerability to SAC inhibitors, and high FOXM1 expression correlated with SAC protein expression and worse outcomes in patients.

Conclusions:

  • The YAP/FOXM1 axis is a central regulator of EMT-associated EGFR TKI resistance.
  • The YAP/FOXM1 axis and SAC components represent therapeutic vulnerabilities for targeting multidrug-resistant phenotypes.
  • Targeting the YAP/FOXM1-SAC pathway may overcome resistance to EGFR TKIs.

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