EML4-ALK G1202R和EML4-ALK L1196M突变通过激活MDM2/MEK/ERK信号轴介导的上皮-间质转化,诱导非小细胞肺癌细胞对克唑替尼产生耐药性

IF 3.3 3区 生物学 Q3 CELL BIOLOGY Cell Biology International Pub Date : 2024-09-24 DOI:10.1002/cbin.12249
Yuying Yang, Huan Yang, Yunhui Gao, Qian Yang, Xinya Zhu, Qianying Miao, Xiaobo Xu, Zengqiang Li, Daiying Zuo
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引用次数: 0

摘要

克唑替尼作为第一代无性淋巴瘤激酶(ALK)抑制剂,能有效改善ALK阳性非小细胞肺癌(NSCLC)患者的生存时间。然而,由于二次突变导致的耐药性,其疗效受到严重限制。G1202R和L1196M是位于ALK激酶结构域的典型突变位点。它们可能会阻碍ALK抑制剂与靶激酶结构域的结合,从而导致患者产生耐药性。然而,这些突变介导耐药的确切机制仍不清楚。在本研究中,我们旨在评估G1202R和L1196M突变如何介导克唑替尼耐药。为了探索耐药机制,我们用A549细胞构建了EML4-ALK G1202R和L1196M突变细胞系。结果显示,与对照(A549-vector)或野生型(A549-EML4-ALK)细胞相比,突变细胞表现出明显的上皮-间质转化(EMT)和转移。随后研究发现,EMT的发生与突变型细胞中鼠双分化2(MDM2)蛋白的高表达和丝裂原活化蛋白激酶(MEK)/细胞外信号调节激酶(ERK)通路的激活有关。下调MDM2抑制了MEK/ERK通路的激活,从而逆转了EMT过程,并显著增强了克唑替尼对突变细胞生长的抑制作用。总之,ALK阳性NSCLC细胞对克唑替尼的耐药性是由G1202R和L1196M突变通过激活MDM2/MEK/ERK信号轴诱导的,促进了EMT过程和转移。这些研究结果表明,MDM2抑制剂与克唑替尼的结合可能是一种潜在的治疗策略。
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EML4-ALK G1202R and EML4-ALK L1196M mutations induce crizotinib resistance in non-small cell lung cancer cells through activating epithelial–mesenchymal transition mediated by MDM2/MEK/ERK signal axis

Crizotinib, as the first-generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK-positive non-small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4-ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial–mesenchymal transition (EMT) and metastasis compared to control (A549-vector) or wild type (A549-EML4-ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway in mutant cells. Down-regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK-positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy.

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来源期刊
Cell Biology International
Cell Biology International 生物-细胞生物学
CiteScore
7.60
自引率
0.00%
发文量
208
审稿时长
1 months
期刊介绍: Each month, the journal publishes easy-to-assimilate, up-to-the minute reports of experimental findings by researchers using a wide range of the latest techniques. Promoting the aims of cell biologists worldwide, papers reporting on structure and function - especially where they relate to the physiology of the whole cell - are strongly encouraged. Molecular biology is welcome, as long as articles report findings that are seen in the wider context of cell biology. In covering all areas of the cell, the journal is both appealing and accessible to a broad audience. Authors whose papers do not appeal to cell biologists in general because their topic is too specialized (e.g. infectious microbes, protozoology) are recommended to send them to more relevant journals. Papers reporting whole animal studies or work more suited to a medical journal, e.g. histopathological studies or clinical immunology, are unlikely to be accepted, unless they are fully focused on some important cellular aspect. These last remarks extend particularly to papers on cancer. Unless firmly based on some deeper cellular or molecular biological principle, papers that are highly specialized in this field, with limited appeal to cell biologists at large, should be directed towards journals devoted to cancer, there being very many from which to choose.
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