Mechanistic and Clinical Overview Cardiovascular Toxicity of BRAF and MEK Inhibitors: JACC: CardioOncology State-of-the-Art Review

Abstract

Rapidly accelerated fibrosarcoma B-type (BRAF) and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors have revolutionized melanoma treatment. Approximately half of patients with melanoma harbor a BRAF gene mutation with subsequent dysregulation of the RAF-MEK-ERK signaling pathway. Targeting this pathway with BRAF and MEK blockade results in control of cell proliferation and, in most cases, disease control. These pathways also have cardioprotective effects and are necessary for normal vascular and cardiac physiology. BRAF and MEK inhibitors are associated with adverse cardiovascular effects including hypertension, left ventricular dysfunction, venous thromboembolism, atrial arrhythmia, and electrocardiographic QT interval prolongation. These effects may be underestimated in clinical trials. Baseline cardiovascular assessment and follow-up, including serial imaging and blood pressure assessment, are essential to balance optimal anti-cancer therapy while minimizing cardiovascular side effects. In this review, an overview of BRAF/MEK inhibitor-induced cardiovascular toxicity, the mechanisms underlying these, and strategies for surveillance, prevention, and treatment of these effects are provided.

Keywords: ACE, angiotensin-converting enzyme; AF, atrial fibrillation; BRAF inhibitor; BRAF, rapidly accelerated fibrosarcoma B-type; CVAE, cardiovascular adverse event; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; LVSD, left ventricular systolic dysfunction; MEK inhibitor; MEK, mitogen-activated extracellular signal-regulated kinase; RAF, rapidly accelerated fibrosarcoma; VEGF, vascular endothelial growth factor; cardio-oncology; cardiovascular toxicity; hypertension; left ventricular systolic dysfunction; melanoma.