ArticleProceedings of the National Academy of Sciences of the United States of America2007
Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 117 citations in OpenAlex.
- Long-term cardiac outcomes of patients with HER2-positive breast cancer treated in the adjuvant lapatinib and/or trastuzumab Treatment Optimization Trial.British journal of cancer · 2020Trial
- Effects of food on the relative bioavailability of lapatinib in cancer patients.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2009Trial
- Signaling pathways and potential therapeutic agents in trastuzumab-induced cardiotoxicity.Apoptosis : an international journal on programmed cell death · 2026Review
- Comprehensive review of non-invasive-treatment-related cardiovascular toxicity in breast cancer.iScience · 2025Review
- Novel insights into cardiovascular toxicity of cancer targeted and immune therapies: Beyond ischemia with non-obstructive coronary arteries (INOCA).American heart journal plus : cardiology research and practice · 2024Article
- Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer.JACC. CardioOncology · 2023Article
- Identification of circRNA-miRNA-mRNA regulatory network and its role in cardiac hypertrophy.PloS one · 2023Article
- A case study of a patient-centered reverse translational systems-based approach to understand adverse event profiles in drug development.Clinical and translational science · 2022Article
- GW-2974 and SCH-442416 modulators of tyrosine kinase and adenosine receptors can also stabilize human telomeric G-quadruplex DNA.PloS one · 2022Article
- Cancer Therapy-Induced Cardiotoxicity-A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy.International journal of molecular sciences · 2021Review
- Phosphorylation of NaThe Journal of membrane biology · 2021Article
- Mechanisms underlying unidirectional laminar shear stress-mediated Nrf2 activation in endothelial cells: Amplification of low shear stress signaling by primary cilia.Redox biology · 2021Review
- Cardiac Safety of Osimertinib: A Review of Data.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Review
- Detrimental effects of chemotherapy on human coronary microvascular function.American journal of physiology. Heart and circulatory physiology · 2019Article
- Article
- Chemotherapeutic Drugs and Mitochondrial Dysfunction: Focus on Doxorubicin, Trastuzumab, and Sunitinib.Oxidative medicine and cellular longevity · 2018Review
- AMP-activated protein kinase and energy balance in breast cancer.American journal of translational research · 2017Review
- Lapatinib resistance in HER2+ cancers: latest findings and new concepts on molecular mechanisms.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Review
- Mechanisms of Cardiotoxicity of Cancer Chemotherapeutic Agents: Cardiomyopathy and Beyond.The Canadian journal of cardiology · 2016Review
- Twenty years of anti-HER2 therapy-associated cardiotoxicity.ESMO open · 2016Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The human EGF receptor (HER) 2 receptor tyrosine kinase is a survival factor for human cardiomyocytes, and its inhibition may explain the increased incidence of cardiomyopathy associated with the anti-HER2 monoclonal antibody trastuzumab (Genentech, South San Francisco, CA), particularly in patients with prior exposure to cardiotoxic chemotherapies e.g., anthracyclines. Here, we show that GW2974 (HER2/EGF receptor tyrosine kinase inhibitor), but not trastuzumab, activates AMP-activated protein kinase (AMPK), initiating a metabolic stress response in human cardiomyocytes that protects against TNFalpha-induced cell death. GW2974 stimulates calcium dependent fatty acid oxidation in vitro and in the myocardium of GW2974-treated rodents. Calcium chelation or siRNA-targeted AMPK knockdown blocks GW2974 induced fatty acid oxidation. In addition, inhibition of AMPK by a specific inhibitor resulted in increased killing of cardiomyocytes. Elucidating the effects of HER2-targeted therapies on AMPK may predict for risk of cardiomyopathy and provide a novel HER2-targeted strategy designed to protect myocardium from the pro-apoptotic effects of pro-inflammatory cytokines released in response to cardiac injury by chemotherapy or acute ischemia.
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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.