title: MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma.
abstract: OBJECTIVE
  To investigate the effects of mTOR inhibition on drug resistance in lung adenocarcinoma after combined radiation and erlotinib therapy.
  
  
  RESULTS
  Combined radiation and erlotinib therapy produced clear radiosensitization effects both in vitro and in vivo; however, tumor cells remained drug resistant. Additionally, combined radiation and erlotinib therapy significantly increased p-AKT and p-P70 levels. After mTOR inhibition, the number of surviving cells significantly decreased compared with that before inhibition, and the in vivo growth curve was significantly reduced.
  
  
  METHODS
  The effects of combined radiation and erlotinib therapy on tumor inhibition and drug resistance were evaluated by in vitro survival curves in PC9 lung adenocarcinoma cell line and in vivo growth curves in nude mouse xenograft tumor model respectively. The association between tumor drug resistance and the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway was measured by western blot, assessing the changes in protein kinase B (AKT), phosphor-AKT (p-AKT), P70, and p-P70 protein levels. MTOR was inhibited using everolimus, and changes in AKT, p-AKT, P70, and p-P70 levels were observed. Furthermore, changes in in vitro survival curves, and in vivo growth curves before and after mTOR inhibition were evaluated to confirm its effects on drug resistance in lung adenocarcinoma after combined radiation and TKI therapy.
  
  
  CONCLUSIONS
  mTOR was associated with drug resistance in lung adenocarcinoma after radiation combined with TKI, and MTOR inhibition reversed drug resistance in lung adenocarcinoma after combined radiation and TKI therapy.
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, China.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Zhuang
authors.affiliation: Department of Radiotherapy, Baotou Cancer Hospital, Neimenggu, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Bai
authors.affiliation: Department of Radiation Oncology, Division of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, and Tianjin Lung Cancer Center, Tianjin, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000532:radiotherapy; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D019008:Drug Resistance, Neoplasm; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; D000068338:Everolimus; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011838:Radiation-Sensitizing Agents; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: drug resistance; erlotinib; everolimus; mTOR; radiation