{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["4(4)"],"submitter":["Beck TC"],"pubmed_abstract":["<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention."],"journal":["JACC. CardioOncology"],"pagination":["535-548"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9700254"],"repository":["biostudies-literature"],"pubmed_title":["Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity."],"pmcid":["PMC9700254"],"pubmed_authors":["Dooley S","Vaena S","Mei Y","Fulmer D","Helke K","Mai L","Weninger J","Vohra A","Guo L","Muise-Helmericks RC","Morningstar JE","Koren N","Biggs R","Holman H","Romeo M","Hyams N","Stayer K","Norris RA","Kwon J","Gensemer C","Dunne J","Moore K","Petrucci T","Stoddard A","Springs K","Mukherjee R","Harvey A","Beck TC","Arhontoulis DC"],"additional_accession":[]},"is_claimable":false,"name":"Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity.","description":"<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Nov","modification":"2025-04-22T09:52:17.651Z","creation":"2025-04-05T23:17:33.122Z"},"accession":"S-EPMC9700254","cross_references":{"pubmed":["36444237"],"doi":["10.1016/j.jaccao.2022.07.009"]}}