Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity

Area of Science:

• Cardiovascular Research
• Oncology Drug Toxicity
• Molecular Biology

Background:

• Trametinib, a MEK1 inhibitor, treats BRAF-mutated melanoma but can cause cardiomyopathy in 11% of patients.
• The molecular mechanisms of trametinib-induced cardiotoxicity remain largely uncharacterized.
• This study investigates the cellular and molecular changes associated with trametinib cardiotoxicity.

Purpose of the Study:

• To test if trametinib causes transcriptomic and cellular changes indicative of oxidative stress.
• To determine if trametinib impairs cardiac function.
• To characterize the molecular landscape of trametinib cardiotoxicity.

Main Methods:

• Mice received trametinib (1 mg/kg/d) with pre- and post-treatment echocardiography.
• Histopathologic and biochemical analyses assessed cardiac changes.
• Human cardiac organoids were used for in vitro cardiotoxicity and recovery assessments.

Main Results:

• Long-term trametinib reduced survival and ejection fraction in mice.
• Histology showed myocardial vacuolization and calcification in 28% of mice.
• RNA sequencing revealed 435 differentially expressed genes and pathways, including IL-6, PI3K/AKT, and JAK/STAT signaling.
• Trametinib hearts had elevated oxidative stress markers, myofibrillar degeneration, and altered apelin receptor and connexin-43 levels.
• In vitro, trametinib impaired human cardiac organoid contractility, with partial recovery upon treatment cessation.

Conclusions:

• Trametinib induces significant cardiac pathology, including oxidative stress and impaired function.
• These findings support exploring drug holidays and alternative strategies to prevent trametinib cardiotoxicity.
• The study provides a molecular basis for understanding and managing trametinib-induced heart damage.