Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells
复制标题
靶向 COX2/MET/TOPK 信号轴诱导吉非替尼耐药 NSCLC 细胞凋亡
DOI：
10.1038/s41419-019-2020-4
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发表时间：
2019-10-14
影响因子：
9
通讯作者：
Zhu, Feng
中科院分区：
文献类型：
--
作者：
Xiao, Juanjuan;Wang, Fei;Zhu, Feng
MET过度活化是酪氨酸激酶抑制剂（TKI）耐药的重要原因之一，但其机制尚不完全清楚。在此，通过免疫组织化学（IHC）分析检测EGFR激活突变型NSCLC中COX 2、TOPK和MET的表达。在体外和离体研究了COX 2、TOPK和MET之间的关系。此外，离体和体内验证了COX 2抑制剂（塞来昔布）、TOPK抑制剂（泮托拉唑）和吉非替尼组合对HCC 827 GR细胞生长的抑制作用。我们发现COX 2和TOPK在EGFR激活的突变型NSCLC中高表达，并且三阳性（COX 2、MET和TOPK）患者的无进展生存期（PFS）短于三阴性患者。然后，我们观察到COX 2-TXA 2信号通路通过AP-1调节MET，从而抑制吉非替尼耐药细胞的凋亡。此外，我们证明，MET可以磷酸化TOPK的Tyr 74，然后防止吉非替尼耐药细胞的凋亡。与这些发现一致，塞来昔布、泮托拉唑和吉非替尼联合用药可诱导吉非替尼耐药细胞凋亡，并在体外和体内抑制肿瘤生长。我们的工作揭示了一种新的COX 2/MET/TOPK信号传导轴，可以防止吉非替尼耐药细胞的凋亡，并表明FDA批准的药物的三重组合将提供一种低成本和实用的策略来克服吉非替尼耐药。
MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined inEGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed inEGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA2signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.