ArticleNature communications2021
HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway.
Article in Nature communications, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
What it found
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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.
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Who cites it
60 citing papers in PubMed, 83 citations in OpenAlex.
- Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.Breast cancer research and treatment · 2024Trial
- Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial.Nature communications · 2023Trial
- Targeting an ASCL1-WNT11-ERK feed-forward loop to overcome pyrotinib resistance in HER2-positive breast cancer.Materials today. Bio · 2026Article
- HER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancer.Nature communications · 2026Article
- Article
- Racial differences in pathologic complete response rate and clinical outcomes following neoadjuvant chemotherapy for breast cancer.Breast cancer research and treatment · 2026Article
- Hotspot mutations in HER2 interfaces destabilize structure, causing breast cancer treatment failure.Oncogene · 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
- Robust CD8Frontiers in immunology · 2026Article
- Factors associated with neoadjuvant therapy insensitivity and its prognostic impact in HER2-positive breast cancer.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2025Article
- Decoding breast cancer: insights into molecular pathways & therapeutic approaches.Discover oncology · 2025Review
- Revealing the Angiogenic Signature ofCancers · 2025Article
- Enhancing HER2-low breast cancer detection with quantitative transcriptomics.NPJ breast cancer · 2025Article
- Efficacy and Predictability of Cyclin-Dependent Kinase 4/6 Inhibitors in HER2-Positive Breast Cancer.Cancers · 2025Review
- Article
- Modeling tumor relapse using proliferation tracing and ablation transgenic mouse.NPJ breast cancer · 2025Article
- Overexpression of miR-29a and miR-29b is involved in imatinib resistance via abrogated NF1 expression and increased ERK1/2 activation in chronic myeloid leukemia cells.Medical oncology (Northwood, London, England) · 2025Article
- APOBEC3 mutagenesis drives therapy resistance in breast cancer.Nature genetics · 2025Article
- Comprehensive Analysis of Oncogenic Somatic Alterations of Mismatch Repair Gene in Breast Cancer Patients.Bioengineering (Basel, Switzerland) · 2025Article
- Diagnostic and therapeutic advances for HER2-expressing or amplified gynecologic cancers.Gynecologic oncology · 2025Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
15 authors at 2 institutions in 2 countries.
Funding
Abstract
Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.
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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.