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YAP-Dependent AXL Overexpression Mediates Resistance to EGFR Inhibitors in NSCLC

Elena Ghiso1, Cristina Migliore2, Vito Ciciriello2

  • 1Candiolo Cancer Institute, FPO-IRCCS, SP 142 km 3.95, 10060, Candiolo, Italy.

Neoplasia (New York, N.Y.)
|November 15, 2017
PubMed

Insights

Yes-associated protein (YAP) activation drives resistance to epidermal growth factor receptor (EGFR) inhibitors in lung cancer. Inhibiting YAP and its downstream target AXL may overcome this resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • The Yes-associated protein (YAP) is a transcriptional co-activator involved in cell growth and apoptosis.
  • YAP dysregulation, particularly overexpression, is linked to tumor progression and metastasis.
  • YAP has emerged as a factor in acquired resistance to targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of YAP in acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer.
  • To identify downstream effectors of YAP responsible for mediating this resistance.
  • To explore the therapeutic potential of targeting the YAP pathway in EGFR-TKI resistant lung cancer.

Main Methods:

  • Utilized EGFR-addicted lung cancer cell lines (HCC4006 and HCC827) rendered resistant to EGFR inhibitors.
  • Performed YAP silencing and overexpression experiments.
  • Investigated the expression and role of the AXL tyrosine kinase receptor as a YAP downstream effector.
  • Assessed the effect of pharmacological and genetic AXL inhibition on drug sensitivity.
  • Analyzed patient samples for YAP and AXL expression upon acquired resistance.

Main Results:

  • Acquired resistance to EGFR inhibitors in lung cancer cell lines was associated with YAP activation.
  • YAP silencing reduced resistance, while YAP overexpression decreased sensitivity to EGFR inhibitors.
  • The AXL tyrosine kinase receptor was identified as a key YAP downstream effector driving resistance.
  • AXL inhibition (pharmacological or genetic) restored sensitivity to EGFR inhibitors in resistant cells.
  • YAP overactivation and AXL overexpression were observed in a lung cancer patient who acquired resistance to EGFR TKIs.

Conclusions:

  • YAP and its downstream target AXL are crucial mediators of acquired resistance to EGFR TKIs in lung cancer.
  • Targeting the YAP/AXL axis, in combination with EGFR inhibition, represents a promising therapeutic strategy for selected non-small cell lung cancer (NSCLC) patients.
  • These findings highlight the clinical relevance of targeting YAP and AXL to overcome resistance to EGFR-targeted therapies.

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