ArticleThe Journal of clinical investigation2023
Inhibition of DPAGT1 suppresses HER2 shedding and trastuzumab resistance in human breast cancer.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 19 citations in OpenAlex.
- HER2 targeted therapy resistance in breast cancer: from molecular landscape to clinical aspects.Science China. Life sciences · 2026Review
- CAF-derived exosomes drive trastuzumab resistance in HER2-positive breast cancer via YAP-USP8-HER2 axis activation.Breast cancer research : BCR · 2026Article
- Structures of Bacterial and Human Phosphoglycosyltransferases Bound to a Common Inhibitor Inform Selective Therapeutics.ACS chemical biology · 2026Article
- Molecular Profiling and Targeted Therapeutic Strategies in Breast Cancer: Clinical Integration of HER2, CDK4/6, and PI3K Inhibition with Trastuzumab, Abemaciclib and Alpelisib.Journal of clinical medicine · 2026Review
- Ebastine targets HER2/HER3 signaling and cancer stem cell traits to overcome trastuzumab resistance in HER2‑positive breast cancer.International journal of molecular medicine · 2026Article
- Spatial molecular analyses reveal key features associated with response to KN026 in advanced HER2-positive breast cancer.British journal of cancer · 2026Article
- New Insights of Muraymycin A1 and Its Analogs as DPAGT1 Inhibitors.Bioorganic chemistry · 2026Article
- Research Advances in Drug Resistance Mechanisms to Anti-HER2 Therapy in HER2-Positive Breast Cancer.Oncology research · 2026Review
- Association between DPAGT1 and Siglec-15 expression and the malignant phenotype of hepatocellular carcinoma.American journal of cancer research · 2026Article
- Structures of bacterial and human phosphoglycosyltransferases bound to a common inhibitor inform selective therapeutics.bioRxiv : the preprint server for biology · 2025Article
- DPAGT1-Perspective as an Anticancer Drug Target.Molecules (Basel, Switzerland) · 2025Review
- Natural and induced epithelial-mesenchymal transition results in epigenetic silencing of HER2 overexpression.Journal of mammary gland biology and neoplasia · 2025Article
- Recent Research Advances in HER2-Positive Breast Cancer Concerning Targeted Therapy Drugs.Molecules (Basel, Switzerland) · 2025Review
- Metabolic hallmarks of trastuzumab resistance.Expert opinion on therapeutic targets · 2025Review
- RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic-nuclear shuttling in human triple-negative breast cancer.Clinical and translational medicine · 2025Article
- PPARG Activation of Fatty Acid Metabolism Drives Resistance to Anti-HER2 Therapies in HER2-Positive Breast Cancer.International journal of biological sciences · 2025Article
- The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review.International journal of molecular sciences · 2024Review
- Glycosylation: mechanisms, biological functions and clinical implications.Signal transduction and targeted therapy · 2024Review
- Article
- Depicting Biomarkers for HER2-Inhibitor Resistance: Implication for Therapy in HER2-Positive Breast Cancer.Cancers · 2024Review
Corrections and comments
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Authors and funding
18 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase - ADAM metallopeptidase domain 10 (ADAM10) - to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.