title: Up-regulation of the Hippo pathway effector TAZ renders lung adenocarcinoma cells harboring EGFR-T790M mutation resistant to gefitinib.
abstract: BACKGROUND
  The T790M mutation of epithelial growth factor receptor (EGFR) is a major cause of the acquired resistance to EGFR tyrosine kinase inhibitor (EGFR-TKIs) treatment for lung cancer patients. The Hippo pathway effector, TAZ, has emerged as a key player in organ growth and tumorigenesis, including lung cancer.
  
  
  RESULTS
  In this study, we have discovered high TAZ expression in non-small cell lung cancer (NSCLC) cells harboring dual mutation and TAZ depletion sensitized their response to EGFR-TKIs. Mechanistically, knockdown of TAZ in T790M-induced resistant cells leaded to reduced anchorage-independent growth in vitro, tumor formation and resistance to gefitinib in vivo, correlated with epithelial-mesenchymal transition (EMT) and suppressed migration and invasion. Furthermore, we confirmed CTGF and AXL, novel EMT markers and potential therapeutic targets for overcoming EGFR inhibitor resistance, as directly transcriptional targets of TAZ.
  
  
  CONCLUSIONS
  Taken together, this study suggests that expression of TAZ is an intrinsic mechanism of T790M-induced resistance in response to EGFR-TKIs. Combinational targeting on both EGFR and TAZ may enhance the efficacy of EGFR-TKIs in acquired resistance of NSCLC.
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China ; Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China.
authors.forename: Yunyan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China.
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Origin Biosciences Inc., 5 New Model Road, Nanjing, Jiangsu 210009 China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu 210029 China.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029 China.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Wu
keywords: EGFR; EMT; Gefitinib; Lung adenocarcinoma; TAZ