ArticleJACC. CardioOncology2022
Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity.
Article in JACC. CardioOncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
20 citing papers in PubMed, 29 citations in OpenAlex.
- The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.Science advances · 2026Article
- Cardiac organoids in toxicology: from construction strategies and research trends to precision screening applications.Stem cell research & therapy · 2026Review
- iPSC-derived cardiac organoids for drug cardiotoxicity evaluation and efficacy prediction in myocardial infarction and cardiac hypertrophy models.Stem cell research & therapy · 2026Article
- Human cardiac organoids: multidimensional integration and clinical translation potential.Frontiers in pharmacology · 2026Review
- Human Cardiac Organoids: Advances and Prospects from Construction to Preclinical Drug Evaluation.Cells · 2025Review
- Inhibition, But Not Depletion, of Erk Signaling Ameliorates Anthracycline-Induced Cardiotoxicity in Zebrafish.JACC. CardioOncology · 2025Article
- Review
- The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.bioRxiv : the preprint server for biology · 2025Article
- Severe symptomatic cardiac dysfunction in a patient with BRAF V600E-mutated metastatic colorectal cancer treated with encorafenib, binimetinib, and cetuximab: a case report.Journal of pharmaceutical health care and sciences · 2025Article
- Cardio-Oncology and Heart Failure: a Scientific Statement From the Heart Failure Society of America.Journal of cardiac failure · 2025Review
- Matters of the Heart: Cardiotoxicity Related to Target Therapy in Oncogene-Addicted Non-Small Cell Lung Cancer.International journal of molecular sciences · 2025Review
- Application of human cardiac organoids in cardiovascular disease research.Frontiers in cell and developmental biology · 2025Review
- Risk Stratification, Screening and Treatment of BRAF/MEK Inhibitors-Associated Cardiotoxicity.Current oncology reports · 2024Review
- Recurrent melanoma 25 years after initial diagnosis, presenting as metastatic disease early after heart transplantation.Cardio-oncology (London, England) · 2024Article
- Real-World Cardiotoxicity in Metastatic Melanoma Patients Treated with Encorafenib and Binimetinib.Cancers · 2024Article
- Applications of 3D organoids in toxicological studies: a comprehensive analysis based on bibliometrics and advances in toxicological mechanisms.Archives of toxicology · 2024Review
- Recent advances in pluripotent stem cell-derived cardiac organoids and heart-on-chip applications for studying anti-cancer drug-induced cardiotoxicity.Cell biology and toxicology · 2023Review
- Post-translational modifications of the apelin receptor regulate its functional expression.AIMS neuroscience · 2023Article
- Melanoma Treatment: The Heart Has Skin in the Game.JACC. CardioOncology · 2022Article
- Targeting noncanonical TGF-beta signaling: inhibition effects on the human keloid fibroblast transcriptome.Itch (Philadelphia, Pa.)Article
Corrections and comments
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Authors and funding
29 authors at 2 institutions in 1 country.
Funding
Abstract
Background: Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)-mutated metastatic melanoma. Roughly 11% of patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, the molecular landscape of trametinib cardiotoxicity has not been characterized. Objectives: The aim of this study was to test the hypothesis that trametinib promotes widespread transcriptomic and cellular changes consistent with oxidative stress and impairs cardiac function. Methods: Mice were treated with trametinib (1 mg/kg/d). Echocardiography was performed pre- and post-treatment. Gross, histopathologic, and biochemical assessments were performed to probe for molecular and cellular changes. Human cardiac organoids were used as an in vitro measurement of cardiotoxicity and recovery. Results: Long-term administration of trametinib was associated with significant reductions in survival and left ventricular ejection fraction. Histologic analyses of the heart revealed myocardial vacuolization and calcification in 28% of animals. Bulk RNA sequencing identified 435 differentially expressed genes and 116 differential signaling pathways following trametinib treatment. Upstream gene analysis predicted interleukin-6 as a regulator of 17 relevant differentially expressed genes, suggestive of PI3K/AKT and JAK/STAT activation, which was subsequently validated. Trametinib hearts displayed elevated markers of oxidative stress, myofibrillar degeneration, an 11-fold down-regulation of the apelin receptor, and connexin-43 mislocalization. To confirm the direct cardiotoxic effects of trametinib, human cardiac organoids were treated for 6 days, followed by a 6-day media-only recovery. Trametinib-treated organoids exhibited reductions in diameter and contractility, followed by partial recovery with removal of treatment. Conclusions: These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.
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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 Socratic graph.