Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer

被引:57
作者
Li, Meng [1 ,2 ]
Yang, Jingyu [1 ,2 ]
Zhou, Wenlong [1 ,2 ]
Ren, Yong [3 ]
Wang, Xiaoxuan [1 ,2 ]
Chen, Huiping [1 ,2 ]
Zhang, Jingyuan [1 ,2 ]
Chen, Junli [1 ,2 ]
Sun, Yuhong [1 ,2 ]
Cui, Lijuan [1 ,2 ]
Liu, Xing [1 ,2 ]
Wang, Lihui [1 ,2 ]
Wu, Chunfu [1 ,2 ]
机构
[1] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China
[2] Shenyang Pharmaceut Univ, Benxi Inst Pharmaceut Res, Shenyang 110016, Peoples R China
[3] Wuhan Gen Hosp, Dept Pathol, Peoples Liberat Army China, Wuhan 430060, Hubei, Peoples R China
基金
中国国家自然科学基金;
关键词
tyrosine kinase inhibitors; non-small cell lung cancer; cancer stem cell; resistance; AKT pathway; FOXM1; STMN1; MESENCHYMAL TRANSITION; STEM-CELLS; RECEPTOR; PROGRESSION; STATHMIN-1; CARCINOMA; CISPLATIN; METASTASIS; EFFICACY; THERAPY;
D O I
10.1038/bjc.2017.292
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Tyrosine kinase inhibitors (TKIs) have demonstrated clinical benefits in the treatment of several tumour types. However, the emergence of TKI resistance restricts the therapeutic effect. This study uses non-small cell lung cancer (NSCLC) to explore the mechanisms contributing to TKI resistance in tumours. Methods: Biological phenotypes and RNA microarray expression data were analysed in NSCLC cells with and without TKI pretreatment. Specific inhibitors and siRNAs were used to validate the direct involvement of an AKT/FOXM1/STMN1 pathway in TKI resistance. Patients' tissues were analysed to explore the clinical importance of FOXM1 and STMN1. Results: In vitro and in vivo studies showed that TKIs induced the enrichment of cancer stem cells (CSC), promoted epithelial to mesenchymal transition (EMT), and conferred multidrug resistance on NSCLC cells in a cell type-and TKI class-dependent manner. Mechanistically, TKIs activated an AKT/FOXM1/STMN1 pathway. The crucial role of this pathway in TKI-induced enrichment of CSC and drug resistance was verified by silencing FOXM1 and STMN1 or blocking the AKT pathway. Additionally, overexpression of STMN1 was associated with upregulation of FOXM1 in advanced NSCLC patients, and STMN1/FOXM1 upregulation predicted a poor outcome. Conclusions: Our findings elucidate an additional common mechanism for TKI resistance and provide a promising therapeutic target for reversing TKI resistance in NSCLC.
引用
收藏
页码:974 / 983
页数:10
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