ArticleGastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association2024
Elucidating molecular mechanisms and therapeutic synergy: irreversible HER2-TKI plus T-Dxd for enhanced anti-HER2 treatment of gastric cancer.
Article in Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers, 1 of them a synthesis that pooled it.
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Who cites it
11 citing papers in PubMed, 1 synthesis or guideline pooled it, 10 citations in OpenAlex.
- Antibody-drug conjugates in HER2-positive advanced or metastatic gastric cancer: a systematic review and meta-analysis.Frontiers in oncology · 2025Pooled it
- Pigmentary Changes Reported with Tyrosine Kinase Inhibitors: A Narrative Review of Mechanisms and Clinical Implications.Clinical drug investigation · 2026Review
- Unlocking the potential: current landscape and future directions of immunotherapy in gastric cancer.Frontiers in immunology · 2026Review
- HER2-ADC and HER2-TKI Overcomes HER2 Amplification as an Acquired Resistance to Zongertinib - A Case Report.Lung Cancer (Auckland, N.Z.) · 2026Article
- Pyrotinib inhibits the tumorigenicity of HER2-positive non-small cell lung cancer by inducing ARIH1/ubiquitin/lysosome-dependent degradation of HER2.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Trastuzumab deruxtecan in the treatment of HER2-positive gastric cancer: a comprehensive review.Future oncology (London, England) · 2025Review
- Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs.Nature communications · 2025Article
- Beamion BCGC-1: phase Ib/II trial of zongertinib for advanced HER2-positive breast or gastroesophageal cancers.Future oncology (London, England) · 2025Article
- The deubiquitinase USP7 stabilizes HER2 expression and promotes breast cancer progression.Neoplasia (New York, N.Y.) · 2025Article
- Pyrotinib induces cell death in HER2-positive breast cancer via triggering HSP90-dependent HER2 degradation and ROS/HSF-1-dependent oxidative DNA damage.Cell stress & chaperones · 2024Article
- Antibody-drug conjugates in gastric cancer: from molecular landscape to clinical strategies.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2024Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
backgroundHER2-targeted therapies have improved the outcomes of HER2-positive gastric cancer (GC), yet resistance remains a challenge. We sought to explore the effects of reversible and irreversible HER2 tyrosine kinase inhibitors (TKIs) alone or in combination with the HER2-targeting antibody drug conjugate trastuzumab deruxtecan (T-Dxd).
methodsThe effects of HER2-TKIs on HER2 and downstream signaling were evaluated via Western blotting. Proteasomal inhibitors and co-immunoprecipitation assays were performed to explore the role of proteasomal degradation in HER2 expression modulation, and immunofluorescence assays were employed to explore mechanisms of HER2 internalization. The synergistic potential of the irreversible HER2-TKI pyrotinib in combination with T-Dxd was validated using growth and viability assays in anti-HER2-positive GC cell cultures and tumor growth and immunohistochemical staining assays in a mouse xenograft model.
resultsOur study revealed that reversible HER2-TKIs elevated HER2 protein levels, whereas irreversible HER2-TKIs decreased them. Pyrotinib triggered HER2 degradation within the proteasome by promoting ubiquitination and dissociation from HSP90. Furthermore, pyrotinib substantially induced HER2 internalization, which led to improved cellular uptake of T-Dxd. The increased T-Dxd uptake was accompanied by greater efficacy in suppressing the growth of GC cells and enhanced anti-tumor effects in an animal model.
conclusionIn summary, our research reveals the molecular mechanisms of irreversible HER2-TKIs in regulating HER2 protein expression by promoting HER2 internalization. These findings advance our comprehension of targeted therapy for GC and provide a promising therapeutic combination strategy with enhanced efficacy against HER2-positive GC.
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