YAP1 is essential for tumor growth and is a potential therapeutic target for EGFR-dependent lung adenocarcinomas
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Ting-Fang Lee1, Yu-Chi Tseng2, Wei-Chin Chang1,3, Yi-Chen Chen2, Yu-Rung Kao4, Teh-Ying Chou1,5, Chao-Chi Ho6 and Cheng-Wen Wu1,2,4
1 Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
2 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
3 Department of Pathology, MacKay Memorial Hospital, Taipei, Taiwan
4 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
5 Department of Pathology, Taipei Veterans General Hospital, Taipei, Taiwan
6 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, Taiwan
Cheng-Wen Wu, email:
Keywords: YAP1, EGFR mutation, lung adenocarcinoma, TKI-resistance
Received: December 21, 2016 Accepted: June 20, 2017 Published: July 27, 2017
Epidermal growth factor receptor (EGFR) mutations are found in lung adenocarcinomas leading to tumor cells proliferation and survival. EGFR tyrosine kinase inhibitors (TKIs) that block EGFR activity are effective therapeutics for EGFR-mutant lung adenocarcinoma patients, but TKI-resistance inevitably occurs. The YES-associated protein (YAP1) transcription coactivator has been implicated as an oncogene and is amplified in human cancers and provides tumor cells strong proliferation and survival cues. This study investigated the roles of YAP1 in lung adenocarcinoma by exploring its regulation and functions mediated by EGFR signaling. In this study, we detected a correlation between YAP1 level and EGFR mutation status in lung adenocarcinoma tissues. Using lung adenocarcinoma cell lines, enhanced YAP1 expression and activity mediated by EGFR signaling was detected through enhanced protein stability. A SRC family protein, YES, was involved in EGFR-regulated YAP1 expression and this pathway was crucial for proliferation in EGFR-dependent cells. Small molecules that reduced YAP1 levels by mechanisms bypassing EGFR signaling were effective in reducing viability in EGFR-dependent cells including those with EGFR T790M, the major cause of TKI-resistance. These observations unveiled the significance of YAP1 in EGFR mutant lung adenocarcinomas and identified YAP1 as a promising therapeutic target for EGFR-dependent lung adenocarcinoma patients, including those with EGFR T790M-caused TKI resistance.
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