Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer.
Activation of an AKT/FOXM1/STMN1 pathway drives resistance to tyrosine kinase inhibitors in lung cancer.
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AKT/FOXM1/STMN1 通路的激活导致肺癌对酪氨酸激酶抑制剂产生耐药性
DOI：
10.1038/bjc.2017.292
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发表时间：
2017-09-26
影响因子：
8.8
通讯作者：
Wu C
中科院分区：
文献类型：
--
作者：
Li M;Yang J;Zhou W;Ren Y;Wang X;Chen H;Zhang J;Chen J;Sun Y;Cui L;Liu X;Wang L;Wu C
背景：酪氨酸激酶抑制剂(TKIs)在治疗几种类型的肿瘤中显示出临床益处。然而，TKI耐药的出现制约了治疗效果。本研究以非小细胞肺癌(NSCLC)为研究对象，探讨肿瘤对TKI耐药的机制。方法：分析TKI处理前后NSCLC细胞的生物学表型和RNA芯片表达数据。用特异性抑制剂和siRNAs验证AKT/FOXM1/STMN1通路在TKI耐药中的直接作用。结果：体内外研究表明，TKI可诱导肿瘤干细胞(CSC)的聚集，促进上皮细胞向间充质转化(EMT)，并以细胞类型和TKI类依赖的方式使NSCLC细胞产生多药耐药。在机制上，TKI激活了AKT/FOXM1/STMN1通路。通过沉默FOXM1和STMN1或阻断AKT通路，证实了该通路在TKI诱导的CSC增加和耐药中的关键作用。此外，在晚期非小细胞肺癌患者中，STMN1的过度表达与FOXM1的上调有关，STMN1/FOXM1的上调预示着不良的预后。结论：我们的发现阐明了TKI耐药的另一个共同机制，并为逆转NSCLC中TKI耐药提供了一个有前景的治疗靶点。
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.
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影响因子：
3.7
作者：
Miyashita A;Fukushima S;Nakahara S;Yamashita J;Tokuzumi A;Aoi J;Ichihara A;Kanemaru H;Jinnin M;Ihn H
通讯作者：
Ihn H
影响因子：
9.7
作者：
Kuang, Xia-Ying;Jiang, He-Sheng;Shao, Zhi-Ming
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影响因子：
7.3
作者：
Morgillo F;Della Corte CM;Fasano M;Ciardiello F
通讯作者：
Ciardiello F
影响因子：
8.8
作者：
Morgillo, F.;Cascone, T.;D'Aiuto, E.;Martinelli, E.;Troiani, T.;Saintigny, P.;De Palma, R.;Heymach, J. V.;Berrino, L.;Tuccillo, C.;Ciardiello, F.
通讯作者：
Ciardiello, F.
影响因子：
17.1
作者：
Sequist LV;Waltman BA;Dias-Santagata D;Digumarthy S;Turke AB;Fidias P;Bergethon K;Shaw AT;Gettinger S;Cosper AK;Akhavanfard S;Heist RS;Temel J;Christensen JG;Wain JC;Lynch TJ;Vernovsky K;Mark EJ;Lanuti M;Iafrate AJ;Mino-Kenudson M;Engelman JA
通讯作者：
Engelman JA