What links BRAF to the heart function? new insights from the cardiotoxicity of BRAF inhibitors in cancer treatment

Abstract

The RAS-related signalling cascade has a fundamental role in cell. It activates differentiation and survival. It is particularly important one of its molecules, B-RAF. B-RAF has been a central point for research, especially in melanoma. Indeed, it lacked effective therapeutic weapons since the early years of its study. Molecules targeting B-RAF have been developed. Nowadays, two classes of molecules are approved by FDA. Multi-target molecules, such as Sorafenib and Regorafenib, and selective molecules, such as Vemurafenib and Dabrafenib. Many other molecules are still under investigation. Most of them are studied in phase 1 trials. Clinical studies correlate B-RAF inhibitors and QT prolongation. Though this cardiovascular side effect is not common using these drugs, it must be noticed early and recognize its signals. Indeed, Oncologists and Cardiologists should work in cooperation to prevent lethal events, such as fatal arrhythmias or sudden cardiac death. These events could originate from an uncontrolled QT prolongation.

Left ventricular ejection fraction decrease related to BRAF and/or MEK inhibitors in metastatic melanoma patients: A retrospective analysis

“…No patient was treated with the combination of encorafenib-binimetinib. The median duration of treatment was 9 months (IQR [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]). 30 patients (34.1%) had a rechallenge after progressive disease under previous treatment with BRAF and/or MEKis.…”

“…8 months (IQR [6][7][8][9]) for patients whose BRAF and/or MEKis were discontinued, and 7 months (IQR [6][7][8][9][10][11][12][13][14][15][16]) for the others. All patients who benefited from a specific treatment had a normalization of LVEF at the end of follow-up.…”

“…5 A new spectrum of side effects has emerged related to these treatments, including several types of cardiovascular adverse events (AEs) such as left ventricular ejection fraction decrease (LVEF-D), QT interval prolongation, hypertension, and peripheral edema. 6,7 LVEF-D induced by BRAF and MEKis, although widely reported in clinical trials, has never been thoroughly described to date and data regarding its management are limited. [8][9][10] The main objective of the study presented herein was therefore to describe the characteristics of LVEF-D in a large cohort of metastatic melanoma patients treated with BRAF and/or MEKis in a real-life setting.…”

The Impact of Pazopanib on the Cardiovascular System

“…The RAF kinases are cardioprotective and promote cardiomyocyte growth and survival. 78,79 Inhibition of these kinases likely contributes to cardiovascular toxicity, as cardiac-specific C-RAF knockout mice have increased cardiomyocyte apoptosis accompanied by left ventricular systolic dysfunction and dilation of the heart. 80 B-RAF activity is a strong mediator of human ether-a-go-go-related gene (hERG) channel expression, 81 and selective inhibition of B-RAF by vemurafenib has been associated with prolonged QT interval in humans.…”

Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond

“…It targets VEGFR 2-3, RET, KIT, PDGFR, and RAF. It can cause high blood pressure and myocardial ischemia [24,29]. Cabozantinib is a potent inhibitor of receptor tyrosine kinases, including VEGF, MET, RET, KIT, Flt-3, AXL and Tie-2.…”