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Published on: August 11, 2017
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.
Abstract:
Yes-associated protein (YAP) is a downstream target of the Hippo pathway and has been found to be oncogenic driving many cancers into developing metastatic phenotypes leading to poor survival outcomes. This study investigated if YAP expression is associated with drug resistance in two non-small cell lung cancer (NSCLC) lines (HCC827 and H1975) generated to become resistant to the EGFR tyrosine kinase inhibitors (EGFR TKI) erlotinib, gefitinib or the T790M-specific osimertinib. We found that acquired EGFR TKI resistance was associated with YAP over-expression (osimertinib-resistant cells) or YAP amplification (erlotinib- and gefitinib-resistant cells) along with EMT phenotypic changes. YAP was localized in the nucleus, indicative of active protein. siRNA-mediated silencing of YAP resulted in re-sensitizing the drug-resistant cells to EGFR TKI compared to the negative siRNA controls (p = <0.05). These results suggest YAP is a potential mechanism of EGFR-TKI resistance in NSCLC and may presents itself as a viable therapeutic target.
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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