ArticleOncoTargets and therapy2019
Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.
Article in OncoTargets and therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 20 citations in OpenAlex.
- Patient-derived organoids from metastatic colorectal cancer mirror tumor heterogeneity and predict patient survival and drug sensitivity.Cell reports. Medicine · 2026Article
- Molecular heterogeneity of ERBB2-altered cancers: A pan-cancer landscape across US and Japanese cohorts.NPJ precision oncology · 2026Article
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- Advances in Molecular Diagnostics and Targeted Therapeutic Approaches in HER-2 Positive Breast Cancer.Asian Pacific journal of cancer prevention : APJCP · 2025Review
- Computational-aided rational mutation design of pertuzumab to overcome active HER2 mutation S310F through antibody-drug conjugates.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- HER2-targeted therapy combined with multidisciplinary management in advanced gallbladder cancer: a case report with 90-month survival.Frontiers in oncology · 2025Article
- MyPathway Human Epidermal Growth Factor Receptor 2 Basket Study: Pertuzumab + Trastuzumab Treatment of a Tissue-Agnostic Cohort of Patients With Human Epidermal Growth Factor Receptor 2-Altered Advanced Solid Tumors.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2024Article
- HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.Frontiers in pharmacology · 2024Review
- Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines.International journal of molecular sciences · 2023Article
- Evaluation of [Molecular pharmaceutics · 2023Article
- A New View of Activating Mutations in Cancer.Cancer research · 2022Article
- Structure-guided and phage-assisted evolution of a therapeutic anti-EGFR antibody to reverse acquired resistance.Nature communications · 2022Article
- Drug-resistant HER2-positive breast cancer: Molecular mechanisms and overcoming strategies.Frontiers in pharmacology · 2022Review
- Clinical updates on tyrosine kinase inhibitors in HER2-positive breast cancer.Frontiers in pharmacology · 2022Review
- Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy. For example, trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target HER2-positive tumour cells. Despite their advances in clinical applications, emerging resistance to these two HER2-targeting antibodies has hindered their further application. Somatic mutations in HER2 receptor have been identified as one of the major reasons for resistance to anti-HER2 antibodies.
methodsWe analysed the frequency of somatic mutations in various tumour types based on TCGA and COSMIC databases. Then, the effect of the most frequent mutation (S310F) on the interaction between pertuzumab and HER2 was analysed by molecular modelling analysis. The effect of the S310F mutation was further evaluated through multiple in vitro binding experiments and antitumour activity assays.
resultsWe found through bioinformatics analysis that S310F, an activating mutation in the HER2 extracellular domain, was the most frequent mutation in HER2. The S310F mutation was shown to confer resistance of HER2-positive tumour cells to pertuzumab treatment. With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue S310. Further functional analyses revealed that the S310F mutation completely abolished pertuzumab binding to HER2 receptor and inhibited pertuzumab antitumour efficacy.
conclusionWe demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.
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