The MEK inhibitor trametinib incurs mitochondrial injury and induces innate immune responses in the mouse heart.

ABSTRACT: Trametinib (Trm) is a highly selective MEK inhibitor that potently and persistently abrogates ERK1/2 activation. Trm initially was used to treat BRAF V600E-mutated melanoma but its FDA-approved indications are expanding rapidly. Trm generally is well tolerated but it can cause dose-limiting cardiomyopathy and heart failure. Here we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part through blunted activity of Electron Transport Sy

SUBMITTER: Fisher-Wellman KH 

PROVIDER: S-EPMC12440023 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature