ArticleEMBO molecular medicine2024
DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer.
Article in EMBO molecular medicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Biologically-informed integration of drug representations for breast cancer treatment using deep learning.Nature communications · 2025Trial
- Targeting an ASCL1-WNT11-ERK feed-forward loop to overcome pyrotinib resistance in HER2-positive breast cancer.Materials today. Bio · 2026Article
- DUSP6/MKP3 as an emerging therapeutic target in glioblastoma.Pharmacological reports : PR · 2026Review
- Review
- HER2 targeted therapy resistance in breast cancer: from molecular landscape to clinical aspects.Science China. Life sciences · 2026Review
- Plasticity, signaling, and metabolic rewiring in melanoma persister cells.Communications biology · 2026Review
- DUSP6 promotes motility, invasion, and tumorigenicity of thyroid cancer cells via IL8-induced neutrophil extracellular traps.Scientific reports · 2026Article
- DUSP6 inhibitor (E/Z)-BCI hydrochloride stimulates glucose clearance and adipose lipolysis in diet-induced obese mice.Genes & diseases · 2026Article
- Research Advances in Drug Resistance Mechanisms to Anti-HER2 Therapy in HER2-Positive Breast Cancer.Oncology research · 2026Review
- Characterization of Drug-Tolerant Persister Cells in Triple-Negative Breast Cancer Identifies a Shared Persistence Program across Treatments and Patients.Cancer research · 2025Article
- Regulation of Milk Production by the MAPK/ERK Pathway in Water Buffalo (Bubalus bubalis): Genomic and Molecular Insights.Veterinary medicine and science · 2025Article
- Dual-Specificity Protein Phosphatases Targeting Extracellular Signal-Regulated Kinases: Friends or Foes in the Biology of Cancer?International journal of molecular sciences · 2025Review
- SSTR2-Targeted Theranostics in Hepatocellular Carcinoma.Cancers · 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
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Authors and funding
14 authors.
Funding
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Abstract
Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon regrowth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.
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