We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells.
- Authors
Xiao, Juanjuan; Wang, Fei; Lu, Hui; Xu, Sanpeng; Zou, Ling; Tian, Qin; Fu, Yang; Lin, Xuan; Liu, Lin; Yuan, Ping; Ni, Xiaofang; Ma, Tengfei; Zeng, Fanfan; Xue, Peipei; Xiu, Ruijuan; Zhang, Jianmin; Ji, Xinying; Hu, Hongbo; Lu, Shangyun; Dai, Hongtian
- Abstract
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 in EGFR-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 in EGFR-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-TXA2 signaling 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.
- Publication
Cell Death & Disease, 2019, Vol 10, Issue 10, pN.PAG
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-019-2020-4