MTOR inhibition reversed drug resistance after combination radiation with erlotinib in lung adenocarcinoma.

Hongqing Zhuang,Zhiyong Yuan,Joe Y Chang,Ping Wang,Jing Bai

doi:10.18632/oncotarget.12423

Abstract

ObjectiveTo investigate the effects of mTOR inhibition on drug resistance in lung adenocarcinoma after combined radiation and erlotinib therapy.ResultsCombined 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.MethodsThe 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.ConclusionmTOR 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.

Highlights

Conclusion: mTOR was associated with drug resistance in lung adenocarcinoma after radiation combined with tyrosine kinase inhibitors (TKIs), and MTOR inhibition reversed drug resistance in lung adenocarcinoma after combined radiation and TKI therapy
Increasing applications for radiotherapy combined with tyrosine kinase inhibitors (TKIs) are evident in clinical practice [1,2,3,4,5], but drug resistance after this combination therapy is common in patients [5,6,7,8,9,10]
TKI drug resistance is a longstanding issue; drug resistance after radiation combined with TKI should have some similarities and differences from single-agent TKI drug resistance, but no current studies have addressed this question

Summary

Introduction

Increasing applications for radiotherapy combined with tyrosine kinase inhibitors (TKIs) are evident in clinical practice [1,2,3,4,5], but drug resistance after this combination therapy is common in patients [5,6,7,8,9,10]. Current treatment of this drug resistance mostly involves treatment of simple TKI drug resistance [6,7,8,9,10]; the mechanism of this drug resistance after the combined radiation and TKI therapy remains unknown. This study investigated the expression changes in the phosphatidylinositol 3-kinase/protein kinase B/ mechanistic target of rapamycin (PI3K-AKT-MTOR) pathway after combined radiation and TKI therapy and this pathway’s inhibition to reverse drug resistance, which could provide potential targets and ideas for resolving clinical drug resistance after combined radiotherapy and TKI

Methods

Results

Conclusion