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

Pharmacol Ther. 2018 Dec:192:65-73. doi: 10.1016/j.pharmthera.2018.06.017. Epub 2018 Jun 28.

Abstract

Many 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 MEK-inhibitors 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.

Keywords: BRAF inhibitor; Cardio-oncology; Cardiovascular toxicity; Decreased ejection fraction; Hypertension; MEK inhibitor.

Publication types

  • Review

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Cardiotoxicity
  • Cardiovascular System / drug effects*
  • Clinical Trials as Topic
  • Humans
  • Melanoma / drug therapy
  • Melanoma / enzymology
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Protein Kinase Inhibitors / adverse effects*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*

Substances

  • Protein Kinase Inhibitors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Mitogen-Activated Protein Kinase Kinases