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Br J Cancer. 2017 Sep 26;117(7):974-983. doi: 10.1038/bjc.2017.292. Epub 2017 Aug 29.

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

Li M1,2, Yang J1,2, Zhou W1,2, Ren Y3, Wang X1,2, Chen H1,2, Zhang J1,2, Chen J1,2, Sun Y1,2, Cui L1,2, Liu X1,2, Wang L1,2, Wu C1,2.

Author information

1
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
2
Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang 110016, China.
3
Department of Pathology, Wuhan General Hospital, People's Liberation Army of China, Wuhan 430060, China.

Abstract

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.

PMID:
28850563
PMCID:
PMC5625681
DOI:
10.1038/bjc.2017.292
[Indexed for MEDLINE]
Free PMC Article

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