ArticleCancer research2023
Acquired Secondary HER2 Mutations Enhance HER2/MAPK Signaling and Promote Resistance to HER2 Kinase Inhibition in Breast Cancer.
Article in Cancer research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 26 citations in OpenAlex.
- Advances in the design and discovery of small-molecule tyrosine kinase inhibitors for breast cancer.RSC advances · 2026Review
- HER2 Alterations in Squamous Cell Lung Cancer: Biology, Therapeutic Landscape, and Emerging Precision Approaches.Cancers · 2026Review
- Oncoprotein CYB561, acting in IRE1-XBP1-SREBF1 and FAK-ERK pathway, promotes breast cancer lipogenesis and progression.Cell death discovery · 2026Article
- Advances in Targeting HER2 across Cancer Subtypes: A Pan-Tumor Approach.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Review
- Comprehensive Molecular Docking and Molecular Dynamics Reveal Inhibitors of HER2 L755S, T798I, and T798M based on a Large Database of Curcumin Derivatives.Asian Pacific journal of cancer prevention : APJCP · 2026Article
- Evolving treatment strategies for HER2-altered non-small-cell lung cancer: the rise of TKIs and ADCs.Frontiers in oncology · 2026Review
- High-throughput characterization of 5886 HER2 variants identifies 112 new in cellulo gain-of-function mutations.Genomics · 2025Article
- Alternative splicing generates HER2 isoform diversity underlying antibody-drug conjugate resistance in breast cancer.Genome research · 2025Article
- Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer.JCI insight · 2025Article
- Advancing Breast Cancer Treatment: The Role of Immunotherapy and Cancer Vaccines in Overcoming Therapeutic Challenges.Vaccines · 2025Review
- New Gain-of-Function Mutations Prioritize Mechanisms of HER2 Activation.medRxiv : the preprint server for health sciences · 2025Article
- Gastric cancer organoids: a promising model for personalized treatment of gastric cancer.Frontiers in cell and developmental biology · 2025Review
- Real-world experience with pertuzumab and trastuzumab combined with chemotherapy in neoadjuvant treatment for patients with early-stage HER2-positive breast cancer: the NEOPERSUR study.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2024Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Review
- Navel orange peel essential oil inhibits the growth and progression of triple negative breast cancer.BMC complementary medicine and therapies · 2024Article
- A novel non-negative Bayesian stacking modeling method for Cancer survival prediction using high-dimensional omics data.BMC medical research methodology · 2024Article
- Impact of Resistance on Therapeutic Design: A Moran Model of Cancer Growth.Bulletin of mathematical biology · 2024Article
- Review
- Advances and Future Perspectives of HER2 Mutations in Non-Small Lung Cancer (NSCLC), Especially in China.Cancer control : journal of the Moffitt Cancer CenterReview
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 4 countries.
Funding
Abstract
HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer. SIGNIFICANCE: HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.
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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.