Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.
Mechanism of Resistance and Novel Targets Mediating Resistance to EGFR and c-Met Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer.
复制标题
抗性和新颖的靶标在非小细胞肺癌中介导对EGFR和C-MET酪氨酸激酶抑制剂的抗性。
DOI：
10.1371/journal.pone.0136155
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Puri N
中科院分区：
文献类型：
--
作者：
Botting GM;Rastogi I;Chhabra G;Nlend M;Puri N
针对EGFR和c-Met的酪氨酸激酶抑制剂（TKI）在非小细胞肺癌（NSCLC）患者中单独或联合给药时最初有效。然而，由于耐药性的发展，TKI的总体疗效有限。因此，阐明EGFR和c-Met TKI耐药的机制以开发更有效的治疗方法是重要的。使用模型NSCLC细胞系H1975和H2170研究EGFR/c-Met TKI耐药机制的相似性和差异。H1975细胞对T790 M EGFR突变呈阳性，其赋予对当前EGFR TKI疗法的抗性，而H2170细胞是EGFR野生型。之前，通过暴露于逐渐增加浓度的TKI，H2170细胞对EGFR TKI厄洛替尼和c-Met TKI SU 11274产生耐药性。在H2170和H1975 TKI抗性细胞中，发现关键Wnt和mTOR蛋白被差异调节。与亲本细胞相比，TKI耐药H2170细胞中Wnt信号转导子活性β-连环蛋白上调。Wnt转录激活因子加塔-6在H2170耐药细胞中表达上调。在H2170厄洛替尼耐药细胞中，观察到无活性GSK 3 β（p-GSK 3 β）的上调，表明Wnt和mTOR途径的激活，否则其活性形式会抑制Wnt和mTOR途径。然而，在H1975细胞中，Wnt调节剂如活性β-catenin、加塔-6和p-GSK 3 β下调。MTT细胞活力测定的其他结果表明，在XAV 939抑制Wnt后，H1975细胞增殖没有显著降低，但依维莫司（mTOR抑制剂）和厄洛替尼联合治疗导致协同细胞生长抑制。因此，在H2170细胞和H1975细胞中，除EGFR和c-Met外，同时抑制关键Wnt或mTOR通路蛋白可能是克服NSCLC患者EGFR和c-Met TKI耐药性的有前景的策略。
Tyrosine kinase inhibitors (TKIs) against EGFR and c-Met are initially effective when administered individually or in combination to non-small cell lung cancer (NSCLC) patients. However, the overall efficacies of TKIs are limited due to the development of drug resistance. Therefore, it is important to elucidate mechanisms of EGFR and c-Met TKI resistance in order to develop more effective therapies. Model NSCLC cell lines H1975 and H2170 were used to study the similarities and differences in mechanisms of EGFR/c-Met TKI resistance. H1975 cells are positive for the T790M EGFR mutation, which confers resistance to current EGFR TKI therapies, while H2170 cells are EGFR wild-type. Previously, H2170 cells were made resistant to the EGFR TKI erlotinib and the c-Met TKI SU11274 by exposure to progressively increasing concentrations of TKIs. In H2170 and H1975 TKI-resistant cells, key Wnt and mTOR proteins were found to be differentially modulated. Wnt signaling transducer, active β-catenin was upregulated in TKI-resistant H2170 cells when compared to parental cells. GATA-6, a transcriptional activator of Wnt, was also found to be upregulated in resistant H2170 cells. In H2170 erlotinib resistant cells, upregulation of inactive GSK3β (p-GSK3β) was observed, indicating activation of Wnt and mTOR pathways which are otherwise inhibited by its active form. However, in H1975 cells, Wnt modulators such as active β-catenin, GATA-6 and p-GSK3β were downregulated. Additional results from MTT cell viability assays demonstrated that H1975 cell proliferation was not significantly decreased after Wnt inhibition by XAV939, but combination treatment with everolimus (mTOR inhibitor) and erlotinib resulted in synergistic cell growth inhibition. Thus, in H2170 cells and H1975 cells, simultaneous inhibition of key Wnt or mTOR pathway proteins in addition to EGFR and c-Met may be a promising strategy for overcoming EGFR and c-Met TKI resistance in NSCLC patients.