ArticleExperimental hematology & oncology2024
Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation.
Article in Experimental hematology & oncology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Fusobacterium nucleatum drives colorectal cancer progression through the circPTBP3/miR-760/PUM1 axis.Oncogene · 2026Article
- Precision Medicine in Treating Lung Cancer: A Narrative Review on Treatments Targeting Oncogenic Genetic Mutations.Cureus · 2026Review
- Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma.Pharmaceutics · 2026Review
- Reply to correspondence 2 on "MET promotes hepatocellular carcinoma development through the promotion of TRIB3-mediated FOXO1 degradation".Clinical and molecular hepatology · 2026Article
- A Review on Anticancer Potential and Structure-Activity Relationships (SAR) of Novel EGFR/HER2 Inhibitors.Current topics in medicinal chemistry · 2026Review
- NAT10-mediated lipid metabolic reprogramming drives EGFR-TKI resistance in non-small cell lung cancer via ac4C-dependent mRNA stabilization.Experimental hematology & oncology · 2025Article
- Targeting mesenchymal-epithelial transition factor signaling in cancer: from genetic alterations to clinical advances and future prospects.Molecular biology reports · 2025Review
- Comparative survival outcomes between EGFR-wildtype and EGFR-mutant lung adenocarcinoma following neoadjuvant chemoimmunotherapy: a retrospective cohort study from national cancer center in China.Translational lung cancer research · 2025Article
- Dickkopf-1 promotes tumor progression of gefitinib- resistant non-small cell lung cancer through cancer cell-fibroblast interactions.Experimental hematology & oncology · 2025Article
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Abstract
backgroundAberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined.
methodsThe gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo.
resultsWe successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case.
conclusionsOur work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.
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