575 Molecular characterization of trametinib-induced cardiotoxicity

Trametinib is a MEK1 inhibitor used in the treatment of BRAF V600E or V600K mutated melanoma. Roughly 10% patients develop cardiomyopathy following chronic trametinib exposure. Although described clinically, molecular landscape trametinib-induced heart failure has not been characterized. We hypothesized that promotes widespread transcriptomic changes consistent with drug-induced cardiotoxicity. Mice treated (1 mg/kg/day) had an average survival time was 69 days. exhibited significant reduction ejection fraction, fractional shortening, and stroke volume, cardiomyopathy-induced failure. Histological analysis unveiled atrophied cardiomyocytes disorganized myocardium preserved sarcomere structure. Intramyocardial calcifications were observed two animals. Bulk RNA-sequencing identified 435 differentially expressed genes (DEGs) treatment. Over-represented DEGs several pathways, including microRNAs cancer, PI3K-Akt signaling, focal adhesion, p53 signaling. Upstream gene predicted IL-6 as regulator 17 relevant DEGs. An Chemicals doxorubicin, cardiotoxic drug, chemical comparable chemical-to-gene regulatory interactions based on patterns downstream expression (80% similarity). Notably, 11-fold downregulation apelin receptor (APJ) The APJ-apelin system regulates cardiac contractility suppression axis associated doxorubicin Studies examining serum levels are ongoing. identification biomarkers predictive cardiotoxicity may reduce need for invasive monitoring improve outcomes receiving metastatic