Cellular and Molecular Mechanisms of MEK1 Inhibitor–Induced Cardiotoxicity

• DOI: 10.1016/j.jaccao.2022.07.009
• Publication Date: 2022-11-16T04:59:54Z
• Authors: Tyler C. Beck; Dimitrios C. Arho...; Jordan E. Morning...; Nathaniel Hyams; Andrew Stoddard; Kendra Springs; Rupak Mukherjee; Kris Helke; Lilong Guo; Kelsey Moore; Cortney Gensemer; Rachel Biggs; Taylor Petrucci; Jennie Kwon; Kristina Stayer; Natalie Koren; Andrew Harvey; Heather Holman; Jaclyn Dunne; Diana Fulmer; Ayesha Vohra; Le Mai; Sarah Dooley; Julianna Weninger; Silvia Vaena; Martin Romeo; Robin C. Muise-He...; Ying Mei; Russell A. Norris
• Keywords: Cardiotoxicity

Trametinib is a MEK1 (mitogen-activated extracellular signal-related kinase 1) inhibitor used in the treatment of BRAF (rapid accelerated fibrosarcoma B-type)–mutated metastatic melanoma. Roughly 11% patients develop cardiomyopathy following long-term trametinib exposure. Although described clinically, molecular landscape cardiotoxicity has not been characterized. The aim this study was to test hypothesis that promotes widespread transcriptomic and cellular changes consistent with oxidative stress impairs cardiac function. Mice were treated (1 mg/kg/d). Echocardiography performed pre- post-treatment. Gross, histopathologic, biochemical assessments probe for changes. Human organoids as an vitro measurement recovery. Long-term administration associated significant reductions survival left ventricular ejection fraction. Histologic analyses heart revealed myocardial vacuolization calcification 28% animals. Bulk RNA sequencing identified 435 differentially expressed genes 116 differential signaling pathways treatment. Upstream gene analysis predicted interleukin-6 regulator 17 relevant genes, suggestive PI3K/AKT JAK/STAT activation, which subsequently validated. hearts displayed elevated markers stress, myofibrillar degeneration, 11-fold down-regulation apelin receptor, connexin-43 mislocalization. To confirm direct cardiotoxic effects trametinib, human 6 days, followed by 6-day media-only Trametinib-treated exhibited diameter contractility, partial recovery removal These data describe pathologic observed cardiotoxicity, supporting exploration drug holidays alternative pharmacologic strategies disease prevention.