title: TGF-β1 induces erlotinib resistance in non-small cell lung cancer by down-regulating PTEN.
abstract: BACKGROUND
  TKI-acquired resistance is a tough obstacle for effectively treating NSCLC patients with EGFR mutant characteristics. T790M mutations and MET amplifications account for 70% of the acquired resistance, but the causes for the remaining 30% need elucidation.
  
  
  METHODS
  We detected TGF-β1and PTEN expression levels in 51 NSCLC patients undergoing EGFR-TKI treatment using Immunohistochemistry (IHC) assay. We examined erlotinib sensitivity, apoptosis rate, and invasion ability in PC-9 cells and PC-9/TGF-β1 cells with CCK-8, flow cytometry, and trans-well assays. We examined and analyzed the AKT and ERK pathways' expression levels using western blot.
  
  
  RESULTS
  High TGF-β1 and low PTEN expression levels were correlated with poor EGFR-TKI sensitivity and overall survival in 51 NSCLC samples. In vitro analysis revealed that TGF-β1 could reduce erlotinib sensitivity, increase anti-apoptosis ability and invasive characteristic in TKI-sensitive PC-9 cell lines by down-regulating PTEN and activating the Akt and ERK pathways.
  
  
  CONCLUSIONS
  The results suggest that TGF-β1 demonstrated another acquired erlotinib resistance by down-regulating PTEN expression.
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Guan
authors.affiliation: Department of Clinical Laborotory, First Affiliated Hospital of Hebei North University, Zhangjiakou 075000, Hebei Province, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
authors.forename: Tongpeng
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. Electronic address: liulianke@medmail.com.cn.
authors.forename: Lianke
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China. Electronic address: shuyongqian1999@126.com.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D020935:MAP Kinase Signaling System; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
chemical_list: D053773:Transforming Growth Factor beta1; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Erlotinib; NSCLC; TGF-β1; TKI resistance