Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity
Tyler C Beck1,2,3, Dimitrios C Arhontoulis1,4, Jordan E Morningstar1,3
1College of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.
Background:
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.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
These data describe pathologic changes observed in trametinib cardiotoxicity, supporting the exploration of drug holidays and alternative pharmacologic strategies for disease prevention.
Insights
Trametinib treatment causes heart damage, including reduced function and oxidative stress, in mice and human organoids. This highlights the need for strategies to prevent or manage trametinib 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.
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