NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors

Marc McGowan1, Lilach Kleinberg1,2, Ann Rita Halvorsen1

  • 1Department of Cancer Genetics, Radium Hospital - Oslo University Hospital, Oslo, Norway.

Genes & Cancer
|July 7, 2017
PubMed

Insights

Yes-associated protein (YAP) promotes cancer metastasis. This study found YAP overexpression or amplification in drug-resistant non-small cell lung cancer (NSCLC) cells, suggesting YAP as a therapeutic target for overcoming EGFR TKI resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Yes-associated protein (YAP) is a key downstream effector of the Hippo pathway.
  • YAP acts as an oncogene, promoting cancer progression and metastasis.
  • Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are standard treatments for non-small cell lung cancer (NSCLC).

Purpose of the Study:

  • To investigate the association between YAP expression and acquired resistance to EGFR TKIs in NSCLC.
  • To determine if YAP plays a role in the development of drug resistance in NSCLC.

Main Methods:

  • Utilized two NSCLC cell lines (HCC827 and H1975) engineered for resistance to erlotinib, gefitinib, or osimertinib.
  • Assessed YAP expression levels (overexpression and amplification) and subcellular localization.
  • Employed siRNA-mediated YAP silencing to evaluate its impact on drug sensitivity.

Main Results:

  • Acquired resistance to EGFR TKIs correlated with YAP overexpression or amplification.
  • YAP was found to be localized in the nucleus, indicating its active state.
  • Silencing YAP expression restored sensitivity to EGFR TKIs in resistant NSCLC cells (p < 0.05).

Conclusions:

  • YAP is implicated as a mechanism driving acquired resistance to EGFR TKIs in NSCLC.
  • Targeting YAP may represent a viable therapeutic strategy to overcome EGFR TKI resistance in NSCLC patients.

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