Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance

Biochem Biophys Res Commun. 2016 May 20;474(1):154-160. doi: 10.1016/j.bbrc.2016.04.089. Epub 2016 Apr 20.


The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.

Keywords: EGFR; KRAS; Lung cancer; Resistance; YAP.

MeSH terms

  • A549 Cells
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / metabolism*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Epidermal Growth Factor / administration & dosage
  • Hippo Signaling Pathway
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism*
  • Phosphoproteins / antagonists & inhibitors
  • Phosphoproteins / metabolism*
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction / drug effects
  • Transcription Factors
  • Treatment Outcome
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Phosphoproteins
  • Protein Kinase Inhibitors
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • epidermal growth inhibitors
  • Epidermal Growth Factor
  • Protein Serine-Threonine Kinases