Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors

Abstract

a b s t r a c t a r t i c l e i n f oMany new drugs have appeared in last years in the oncological treatment scenario. Each drug carries an important set of adverse events, not less, cardiovascular adverse events. This aspect is even more important considering the increasing use of combination therapies with two drugs, or three drugs as in some ongoing clinical trials. Besides it represents a growing problem for Cardiologists, that face it in every day clinical practice and that will face it probably more and more in the coming years. This work reviews the mechanism of action of BRAF-inhibitors and MEKinhibitors used together, the pathophysiological mechanisms that lead to cardiovascular toxicity. Particularly, it focuses on hypertension and ejection fraction reduction development. Then, it follows the examination of published data for each combination therapy. A Literature research was carried out using Pubmed selecting review articles, original studies and clinical trials, but mainly focusing on phase 3 studies. This work aims to summarize the knowledge about BRAF-inhibitor and MEK-inhibitor treatment and its cardiovascular toxicity to make it usable and give the basic tools to Cardiologists and Oncologists for a better management of cancer patient undergoing this treatment. Besides a deeper knowledge of the cardiovascular adverse events linked to this treatment and the magnitude of their expression and frequency can lead to a targeted cardiological treatment.

Cardiac tamponade induced by dabrafenib and trametinib combination therapy for melanoma

“…In the phase III COMBI-d trial, treatment related cardiac adverse events were reported as decrease in left ventriclar ejection fraction in 5% of patients. [ 3 ]…”

“…The BRAF inhibitors are reported to cause hypertension, and QT interval prolongation as seen on ECG. [ 3 ] Unlike Dabrafenib we have reports of vemurafenib induced pericarditis associated with effusions and cardiac tamponade. [ 7 ] Mahoney et al demonstrated that appropriate treatment of cardiac tamponade and vemurafenib discontinuation, resulted in complete resolution with the ability to resume treatment.…”

“…Increased use of Dabrafenib and Trametinib will reveal more cardiovascular complications which could be attributed to the “two hit hypothesis.” [ 3 ] The cardiac toxicity is sum of two events like hypertension, cardiac ischemia or exposure to toxic drugs resulting in clinically apparent cardiac injury caused by the BRAF/MEK inhibitors. [ 5 ]…”

“…[ 2 ] Trametinib is reported to cause hypertension, peripheral edema, and cardiomyopathy, which is attributed to the inhibition of the cardioprotective function of the MAPK pathway. [ 3 ] Combination therapy increased the cardiovascular toxicity, causing decreased ejection fraction, pulmonary embolism, cardiomyopathy, hypertension, and hypotension. [ 3 , 4 ] It is postulated that the disruption of the MEK-ERK axis explains the pathophysiology of cardiovascular toxicity.…”

“…[ 3 ] Combination therapy increased the cardiovascular toxicity, causing decreased ejection fraction, pulmonary embolism, cardiomyopathy, hypertension, and hypotension. [ 3 , 4 ] It is postulated that the disruption of the MEK-ERK axis explains the pathophysiology of cardiovascular toxicity. [ 5 ]…”