Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity.

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.
Competing Interests: Dr Norris was supported by grants from the National Institutes of Health (NIH) (R01-HL131546, R01-HL149696, R01-HL122906, R01-HL162913, and P30-1034444), the American Heart Association (19TPA34850095, 20SRG35540029, and 19TPA34900016), and the South Carolina Translational Research Institute (TD1612). Dr Mei was supported by grants from the NIH (R01HL133308), the National Science Foundation (EPS- 0903795), and the U.S. Department of Veterans Affairs Merit Review (I01 BX002327). Dr Beck was supported by training grants from the NIH (F31-HL158243 and T32-HL007260). Mr Arhontoulis and Mr Morningstar were supported by a training grant from the NIH (T32-HL007260). Dr Gensemer was supported by grants from the NIH (T32GM132055 and T32HL007260). The work at Medical University of South Carolina was performed in a facility constructed with support from NIH grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Additional funding support was provided by the Translational Sciences Lab in part by pilot research funding (Hollings Cancer Center’s Cancer Center Support Grant P30 CA138313 at the Medical University of South Carolina). The views expressed in this paper are those of the authors and do not necessarily represent the view of the National Heart, Lung, and Blood Institute, the NIH, or the American Heart Association. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: Trametinib produces a cardiomyopathy characterized by elevated IL-6, increased oxidative stress, decreased cardiac contractility, loss of cell-to-cell communication, and myofibrillar breakdown. Our data support that these changes may be reversible over time. TRANSLATIONAL OUTLOOK: Elevations in IL-6 and oxidative stress, as well as transcriptomic changes associated with cardiac function, were observed. Future studies should examine the effects of tocilizumab on cardiotoxicity, drug resistance, and anticancer efficacy. Drug holidays may be used to prevent pathologic remodeling, as well as drug resistance. Last, the use of antioxidant drugs, including agents such as dexrazoxane, could be studied in the prevention of trametinib-induced cardiotoxicity.
(© 2022 Published by Elsevier on behalf of the American College of Cardiology Foundation.)