ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 77 citations in OpenAlex.
- Neratinib Efficacy and Circulating Tumor DNA Detection ofClinical cancer research : an official journal of the American Association for Cancer Research · 2017Trial
- Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.Breast cancer research : BCR · 2017Trial
- 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
- Advances in predicting breast cancer driver mutations: Tools for precision oncology (Review).International journal of molecular medicine · 2025Review
- Feasibility Study of Pyrrolitinib-Based Dual-Target Therapy for Neoadjuvant Treatment of HER2-Positive Breast Cancer Patients.Breast cancer (Dove Medical Press) · 2024Article
- Clinical characteristics and treatment outcomes of HER2 mutation and HER2 fusion in 22 patients with advanced breast cancer.Thoracic cancer · 2023Article
- Exosomal Linc00969 induces trastuzumab resistance in breast cancer by increasing HER-2 protein expression and mRNA stability by binding to HUR.Breast cancer research : BCR · 2023Article
- Reckoning apigenin and kaempferol as a potential multi-targeted inhibitor of EGFR/HER2-MEK pathway of metastatic colorectal cancer identified using rigorous computational workflow.Molecular diversity · 2022Article
- Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021.Journal of hematology & oncology · 2022Review
- HER2 c-Terminal Fragments Are Expressed via Internal Translation of the HER2 mRNA.International journal of molecular sciences · 2022Article
- Integrated approach to functional analysis of an ERBB2 variant of unknown significance detected by a cancer gene panel test.Cellular oncology (Dordrecht, Netherlands) · 2022Article
- circCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer.Molecular cancer · 2022Article
- Improving HER2 testing reproducibility in HER2-low breast cancer.Cancer drug resistance (Alhambra, Calif.) · 2022Article
- Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2.Pharmaceuticals (Basel, Switzerland) · 2021Article
- Phase I Clinical Trial of an Autologous Dendritic Cell Vaccine Against HER2 Shows Safety and Preliminary Clinical Efficacy.Frontiers in oncology · 2021Article
- Dissecting the molecular recognition of dual lapatinib derivatives for EGFR/HER2.Journal of computer-aided molecular design · 2020Article
- Attenuation of p53 mutant as an approach for treatment Her2-positive cancer.Cell death discovery · 2020Review
- Novel Approaches and Challenges of Discovery of Exosite Modulators of a Disintegrin and Metalloprotease 10.Frontiers in molecular biosciences · 2020Review
- Emergence ofThe oncologist · 2019Review
- miR-200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer.Journal of cellular and molecular medicine · 2019Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
purposeMutations in receptor tyrosine kinase (RTK) genes can confer resistance to receptor-targeted therapies. A T798M mutation in the HER2 oncogene has been shown to confer resistance to the tyrosine kinase inhibitor (TKI) lapatinib. We studied the mechanisms of HER2-T798M-induced resistance to identify potential strategies to overcome that resistance. EXPERIMENTAL
designHER2-T798M was stably expressed in BT474 and MCF10A cells. Mutant cells and xenografts were evaluated for effects of the mutation on proliferation, signaling, and tumor growth after treatment with combinations of inhibitors targeting the EGFR/HER2/HER3/PI3K axis.
resultsA low 3% allelic frequency of the T798M mutant shifted 10-fold the IC50 of lapatinib. In mutant-expressing cells, lapatinib did not block basal phosphorylation of HER2, HER3, AKT, and ERK1/2. In vitro kinase assays showed increased autocatalytic activity of HER2-T798M. HER3 association with PI3K p85 was increased in mutant-expressing cells. BT474-T798M cells were also resistant to the HER2 antibody trastuzumab. These cells were sensitive to the pan-PI3K inhibitors BKM120 and XL147 and the irreversible HER2/EGFR TKI afatinib but not the MEK1/2 inhibitor CI-1040, suggesting continued dependence of the mutant cells on ErbB receptors and downstream PI3K signaling. BT474-T798M cells showed increased expression of the EGFR ligands EGF, TGFα, amphiregulin, and HB-EGF. Addition of the EGFR neutralizing antibody cetuximab or lapatinib restored trastuzumab sensitivity of BT474-T798M cells and xenografts, suggesting that increased EGFR ligand production was causally associated with drug resistance.
conclusionsSimultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene-amplified breast cancer cells harboring T798M mutant alleles.
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Registered trials
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