NSCLC depend upon YAP expression and nuclear localization after acquiring resistance to EGFR inhibitors
Marc McGowan1, Lilach Kleinberg1,2, Ann Rita Halvorsen1, Åslaug Helland1,3, and Odd Terje Brustugun1,4
1 Department of Cancer Genetics, Radium Hospital – Oslo University Hospital, Oslo, Norway
2 Department of Pathology, Oslo University Hospital, Oslo, Norway
3 Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
4 Section of Oncology, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
Correspondence:
Odd Terje Brustugun, email:
Keywords: Drug-resistance, NSCLC, YAP, EGFR, EMT
Received: April 16, 2017 Accepted: May 21, 2017 Published: May 23, 2017
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.
