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Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

Juanjuan Xiao1,2, Fei Wang1, Hui Lu1

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.

Cell Death & Disease
|October 16, 2019
PubMed

Insights

MET overactivation causes resistance to tyrosine kinase inhibitors (TKIs) in lung cancer. A novel COX2/MET/TOPK pathway inhibits apoptosis, but combining celecoxib, pantoprazole, and gefitinib overcomes this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • MET overactivation is a key mechanism of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC).
  • The precise molecular mechanisms underlying MET-driven TKI resistance remain incompletely understood.
  • EGFR-activating mutations are common in NSCLC, and resistance to EGFR inhibitors like gefitinib is a significant clinical challenge.

Purpose of the Study:

  • To investigate the role of COX2, TOPK, and MET in EGFR-mutated NSCLC with gefitinib resistance.
  • To elucidate the signaling axis connecting COX2, MET, and TOPK in the context of TKI resistance.
  • To evaluate the therapeutic potential of combining COX2, TOPK, and gefitinib inhibitors to overcome gefitinib resistance.

Main Methods:

  • Immunohistochemical (IHC) analysis of COX2, TOPK, and MET expression in NSCLC patient samples.
  • In vitro and ex vivo experiments to explore the relationship between COX2, MET, and TOPK.
  • In vivo studies using mouse models to assess the efficacy of drug combinations.

Main Results:

  • Elevated COX2 and TOPK expression observed in EGFR-mutated NSCLC.
  • Shorter progression-free survival (PFS) in patients with triple-positive (COX2, MET, TOPK) expression.
  • Identified a COX2-TXA2-MET-AP1 signaling pathway inhibiting apoptosis in gefitinib-resistant cells.
  • Demonstrated MET-mediated phosphorylation of TOPK at Tyr74, preventing apoptosis.
  • Combination therapy (celecoxib, pantoprazole, gefitinib) induced apoptosis and inhibited tumor growth in vitro, ex vivo, and in vivo.

Conclusions:

  • A novel COX2/MET/TOPK signaling axis contributes to gefitinib resistance by inhibiting apoptosis in NSCLC.
  • Targeting this axis with a combination of FDA-approved drugs offers a promising strategy to overcome TKI resistance.
  • This triple combination therapy presents a potentially low-cost and clinically practical approach for treating resistant NSCLC.

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