ArticleBritish journal of cancer2022
Inhibition of PFKFB3 in HER2-positive gastric cancer improves sensitivity to trastuzumab by inducing tumour vessel normalisation.
Article in British journal of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- The evolving landscape of the Warburg effect in gastric cancer: From molecular mechanisms to targeted therapy.Clinical and translational medicine · 2026Review
- HER2 deficiency causes a developmental disorder with growth retardation and craniofacial malformations.The Journal of clinical investigation · 2026Article
- Tumor microenvironment dynamics in gastric cancer pathogenesis and therapeutic resistance.Molecular cancer · 2026Review
- Spatial Fibroblast-Macrophage Niches in Gastric Cancer: Mechanisms of Immune Exclusion, Therapeutic Resistance, and Targeted Intervention.OncoTargets and therapy · 2026Review
- PFKFB3 as a multifaceted driver and therapeutic target in castration-resistant prostate cancer.Cell death & disease · 2025Article
- Metabolic hallmarks of trastuzumab resistance.Expert opinion on therapeutic targets · 2025Review
- Warburg effect and lactylation in cancer: mechanisms for chemoresistance.Molecular medicine (Cambridge, Mass.) · 2025Review
- HER2-positive gastric cancer: from targeted therapy to CAR-T cell therapy.Frontiers in immunology · 2025Review
- Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- Article
- HER2International journal of oncology · 2024Review
- HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments.Cancers · 2024Review
- HER2 in Metastatic Colorectal Cancer: Pathology, Somatic Alterations, and Perspectives for Novel Therapeutic Schemes.Life (Basel, Switzerland) · 2022Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMultiple mechanisms have been proposed that lead to reduced effectiveness of trastuzumab in HER2-positive gastric cancer (GC), yet resistance to trastuzumab remains a challenge in clinics.
methodsWe established trastuzumab-resistant cells and patient-derived xenografts models to measure metabolic levels and vascular density and shape. The HER2-positive GC patient samples were used to determine clinical significance. We also measured protein expression and phosphorylation modifications to determine those alterations related to resistance. In vivo studies combining inhibitor of PFKFB3 with trastuzumab corroborated the in vitro findings.
resultsThe 6-phosphofructo-2-kinase (PFKFB3)-mediated trastuzumab resistance pathways in HER2-positive GC by activating the glycolytic pathway. We also found vessels are chaotic and destabilised in the tumour during the trastuzumab resistance process. Inhibition of PFKFB3 significantly diminished tumour proliferation and promoted vessel normalisation in the patient-derived xenograft model. Mechanistically, PFKFB3 promoted the secretion of CXCL8 into the tumour microenvironment, and phosphorylated Ser1151 of ERBB2, enhancing the transcription of CXCL8 by activating the PI3K/AKT/NFκB p65 pathway.
conclusionsOur current findings discover that PFKFB3 inhibitors might be effective tools to overcome adjuvant therapy resistance in HER2-positive GC and reshaping the microenvironment by normalising tumour vessels is a novel strategy to overcome trastuzumab resistance.
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