Cutaneous malignant melanoma is a form of skin cancer that develops from pigment-producing melanocytes. In the United States, melanoma is the fifth most common cancer, with nearly 200,000 adults diagnosed annually. The prognosis for patients with metastatic stage IV melanoma is poor, with a 5-year survival rate of roughly 30%. Approximately 60% of melanomas harbor activating mutations in BRAF (rapid accelerated fibrosarcoma B-type), a serine/threonine protein kinase, leading to constitutive activation of the mitogen activation protein kinase pathway. Roughly 90% of BRAF mutations involve the substitution of glutamic acid for valine at amino acid 600. As such, the BRAF inhibitors dabrafenib, vemurafenib, and encorafenib are routinely used to treat patients with unresectable stage III or stage IV BRAF-mutated metastatic melanoma. 

The use of vemurafenib as monotherapy in metastatic melanoma was associated with a relative reduction of 63% in the risk for death and of 74% in the risk for either death or disease progression compared to dacarbazine. Although promising, BRAF inhibition quickly leads to compensatory activation of MEK1 (mitogen-activated extracellular signal-related kinase kinase 1), promoting drug resistance.5 As such, the MEK1 inhibitors trametinib, cobimetinib, and binimetinib have been approved for concomitant use in patients with advanced disease. Concurrent BRAF/MEK1 inhibition has led to dramatic improvements in response rate, progression-free survival, and overall survival in comparison with historical treatments. Clinical data suggest the use of MEK1 inhibitors may be limited by cardiovascular toxicities, such as systemic hypertension, cardiomyopathy, venous thromboembolism, atrial fibrillation, and QT interval prolongation. Of note, roughly 11% of patients treated with trametinib develop cardiomyopathy, defined as a reduction in ejection fraction >10% as determined by echocardiography.9 Evidence suggests that MEK1/ERK1/2 (extracellular signal-regulated protein kinase 1/2) signaling is critical for cardiomyocyte homeostasis and cardiac stress responses; however, the cellular and molecular changes that occur during MEK1 inhibitor–induced cardiotoxicity have not yet been characterized.

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Mishita
Jornal co-ordinator
Journal of Heart and Cardiovascular Research