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.
Highlights
Lung cancer is the most frequent cancer and the most common cause of cancer-related deaths worldwide[1]
COX2 is the upstream regulator of MET in HCC827GR cells and epidermal growth factor receptor (EGFR)-activating mutated Nonsmall cell lung cancer (NSCLC)
To confirm whether COX2 could regulate MET expression in NSCLC, we first analyzed the expression of COX2 in HCC827 and HCC827GR cells (MET amplification, gefitinib resistance18)
Summary
Lung cancer is the most frequent cancer and the most common cause of cancer-related deaths worldwide[1]. MET (hepatocyte growth factor receptor, HGFR) overactivation is one of the crucial reasons for TKI resistance. It has been reported that MET gene amplification, activating gene mutations, and MET overexpression can lead to MET overactivation, and that these changes were all significantly associated with unfavorable prognosis in NSCLC4,5. MET encodes a transmembrane tyrosine kinase receptor for hepatocyte growth factor (HGF) and it can be activated by HGF or by the Src/FAK or EGFR signaling pathway in lung cancer[6,7]. Activated MET interacts with several adaptor proteins, such as STAT3, PI3K, or Src, subsequently activating the mitogenactivated protein kinase and mammalian target of rapamycin pathways to mediate proliferation, apoptosis, and Official journal of the Cell Death Differentiation Association
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