ArticleCancer biology & therapy2014
Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition.
Article in Cancer biology & therapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 53 citations in OpenAlex.
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- HER2 Antibody-Drug Conjugates Are Active against Desmoplastic Small Round Cell Tumor.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- A Non-Canonical p75HER2 Signaling Pathway Underlying Trastuzumab Action and Resistance in Breast Cancer.Cells · 2024Article
- Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors.Chinese journal of cancer research = Chung-kuo yen cheng yen chiu · 2024Article
- HER2-targeted therapies in cancer: a systematic review.Biomarker research · 2024Review
- Development of High-Loading Trastuzumab PLGA Nanoparticles: A Powerful Tool Against HER2 Positive Breast Cancer Cells.International journal of nanomedicine · 2023Article
- Article
- HER2 Expression in Peritoneal Dissemination of High-Grade Serous Ovarian Carcinoma: A Comparative Study of Immunohistochemical Reactivity Using Four HER2 Antibodies.Journal of clinical medicine · 2022Article
- Resistance to Trastuzumab.Cancers · 2022Review
- Article
- Non-phosphorylated Tyr-1248 form of human epidermal growth factor receptor 2 (HER2) predicts resistance to trastuzumab therapy and poor disease-free survival of HER2-positive breast cancer patients.Croatian medical journal · 2022Article
- Regulation, targets and functions of CHK.Frontiers in cell and developmental biology · 2022Review
- Neuregulin 4 Boosts the Efficacy of Anti-ERBB2 Neutralizing Antibodies.Frontiers in oncology · 2022Article
- Sortilin-related receptor is a druggable therapeutic target in breast cancer.Molecular oncology · 2022Article
- UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells.Cancer chemotherapy and pharmacology · 2021Article
- Review
- Rac inhibition as a novel therapeutic strategy for EGFR/HER2 targeted therapy resistant breast cancer.BMC cancer · 2021Article
- Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers.Antibodies (Basel, Switzerland) · 2021Article
- Trastuzumab effects depend on HER2 phosphorylation in HER2-negative breast cancer cell lines.PloS one · 2020Article
- Targeting Rac and Cdc42 GEFs in Metastatic Cancer.Frontiers in cell and developmental biology · 2020Review
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The inhibitory effect of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of ErbB2, is associated with its ability to induce ErbB2-Y1248 phosphorylation, and the status of phosphorylated ErbB2-Y1248 (ErbB2-pY1248) may correlate with the sensitivity of breast cancers to trastuzumab. The mechanisms of which remain unclear. Here, we show that binding of trastuzumab to ErbB2 activates ErbB2 kinase activity and enhances ErbB2-Y1248 phosphorylation in trastuzumab-sensitive breast cancer cells. This in turn increases the interaction between ErbB2 and non-receptor Csk-homologous kinase (CHK), leading to growth inhibition of breast cancer cells. Overexpression of CHK mimics trastuzumab treatment to mediate ErbB2-Y1248 phosphorylation, Akt downregulation, and growth inhibition of trastuzumab-sensitive breast cancer cells. CHK overexpression combined with trastuzumab exerts an additive effect on cell growth inhibition. We further demonstrate that positive ErbB2-pY1248 staining in ErbB2-positive breast cancer biopsies correlates with the increased trastuzumab response in trastuzumab neoadjuvant settings. Collectively, this study highlights an important role for ErbB2-pY1248 in mediating trastuzumab-induced growth inhibition and trastuzumab-induced interactions between CHK and ErbB2-pY1248 is identified as a novel mechanism of action that mediates the growth inhibition of breast cancer cells. The novel mechanistic insights into trastuzumab action revealed by this study may impact the design of next generation of therapeutic monoclonal antibodies targeting receptor tyrosine kinases, as well as open new avenues to identify novel targets for the treatment of ErbB2-positive cancers.
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