MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma
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Hongqing Zhuang1,*, Jing Bai2,*, Joe Y. Chang3, Zhiyong Yuan1, Ping Wang1
1Department 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
2Department of Radiotherapy, Baotou Cancer Hospital, Neimenggu, China
3Department of Radiation Oncology, Division of Radiation Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA
*These authors have contributed equally to this work
Hongqing Zhuang, email: [email protected]
Keywords: erlotinib, radiation, drug resistance, everolimus, mTOR
Received: April 19, 2016 Accepted: September 20, 2016 Published: October 04, 2016
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.
Conclusion: 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.
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