ArticleCancer discovery2026
Trastuzumab Deruxtecan Resistance via Loss of HER2 Expression and Binding.
Article in Cancer discovery, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
30 citing papers in PubMed.
- A modular framework for antibody-drug conjugate biomarkers.Nature reviews. Clinical oncology · 2026Review
- Optimizing the ER Cutoff in HER2-Positive Breast Cancer: ER ≥ 50% Predicts Low pCR Rates and Resistance to Antibody-Drug Conjugates in the Neoadjuvant Setting.Cancer medicine · 2026Article
- Antibody-drug conjugates in breast cancer: redefining targeted therapy.The Journal of clinical investigation · 2026Review
- Antibody-drug conjugate engineering: from design to efficacy and safety.Signal transduction and targeted therapy · 2026Review
- Intracellular Nanopharmacology of Trastuzumab Deruxtecan Reveals Lysosome-Centered Organelle Vulnerabilities in HER2-Positive Breast Cancer Cells.ACS nano medicine · 2026Article
- Real-world outcomes of datopotamab deruxtecan after trastuzumab deruxtecan in hormone receptor-positive, HER2-negative metastatic breast cancer.Breast cancer (Tokyo, Japan) · 2026Article
- Circulating tumour cells for guiding antibody‒drug conjugate therapy: Role of artificial intelligence.Clinical and translational medicine · 2026Review
- Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer: Real-World Outcomes and Treatment Transition Patterns in a Chinese Cohort.Current oncology (Toronto, Ont.) · 2026Article
- Article
- Daraxonrasib and Beyond: Pan-RAS Inhibition, Resistance, and Next-Generation Strategies.Cancer science · 2026Review
- HER2 Heterogeneous Breast Cancer Models Reveal Novel Therapeutic Targets and Subclonal Dynamics during Evolution to Resistance to HER2-Targeted Therapies.Cancer discovery · 2026Article
- Targeting TROP2 and Exploiting AUNIP as a Determinant of ADC Cytotoxicity and Chemosensitivity in HNSCC and ESCA Cancers.Molecular carcinogenesis · 2026Article
- Emerging role of human epidermal growth factor 2-low status in the prognosis and management of triple-negative breast cancer: a narrative review.Translational cancer research · 2026Review
- Advancing antibody drug conjugates in gastrointestinal cancers.British journal of cancer · 2026Review
- From Unmet Medical Need to Drug Candidate: A Translational Therapeutic Development Roadmap Illustrated by Dual-Payload Antibody-Drug Conjugates.Biomolecules · 2026Review
- Clinical Outcomes for Patients who Received Both Trastuzumab Deruxtecan (T-DXd) and Trastuzumab Emtansine (T-DM1) for HER2-Mutant non-Small Cell Lung Cancer.JTO clinical and research reports · 2026Article
- Overcoming Resistance in Triple-Negative Breast Cancer: A Translational Perspective on Next-Generation DNA Damage Response Inhibitors and Synthetic Lethality.Molecules (Basel, Switzerland) · 2026Review
- Dynamic monitoring of antibody drug conjugates targeting TROP2 or HER2 in breast cancer using circulating tumor cells.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Real-World Effectiveness and Safety of Tucatinib, Trastuzumab, and Capecitabine in HER2-Positive Advanced Breast Cancer: A Multicenter Portuguese Study.European journal of breast health · 2026Article
- Review
Corrections and comments
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Authors and funding
17 authors.
Funding
Abstract
Trastuzumab Deruxtecan (T-DXd) is clinically beneficial in HER2-positive and HER2-low metastatic breast cancer. However, therapeutic resistance emerges over time in most patients, with poorly defined resistance mechanisms. Through a molecular characterization of paired patient specimens before and after T-DXd treatment, we found that 49% cases had major decreases in HER2 expression at progression, and among them, 52% exhibited complete HER2 loss. Using isogenic model systems, we demonstrated that decreases in HER2 expression corresponded to reductions in T-DXd internalization and major increases in drug IC50 value for tumor growth inhibition. We further identified and validated ERBB2 mutations in the trastuzumab binding interface (V597M and P593R) that promoted T-DXd resistance. As a strategy to overcome impaired T-DXd binding and internalization, we tested low-dose combinations of T-DXd with TROP2-directed antibody-drug conjugates (ADC) and found that these could more uniformly deliver DXd payloads and thereby overcome resistance mediated by HER2 loss. SIGNIFICANCE: The mechanisms underlying clinical T-DXd resistance have not been established. We now report on two mechanisms of resistance that converge on loss of target binding and propose combinations of distinct ADCs with shared payloads as a strategy to overcome resistance by enhancing intratumor delivery. See related commentary by O'Meara and Tarantino, p.195.
Indexed as
Identifiers
What Socratic holds
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 Socratic graph.