Inhibiting the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in cancer and the heart: for better or worse, in sickness and health?

Clerk, A. ORCID: https://orcid.org/0000-0002-5658-0708, Amadi, S. U., Smith, S. J. and Sugden, P. H. (2024) Inhibiting the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade in cancer and the heart: for better or worse, in sickness and health? International Journal of Drug Discovery and Pharmacology. ISSN 2653-6234 doi: 10.53941/ijddp.2024.100006

Abstract/Summary

The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are the prototypic mitogen-activated protein kinases, first discovered and investigated in the context of cell division and their role in cancer. ERK1/2 are phosphorylated and activated by upstream kinases, MEK1/2 (also known as MKK1/2) that are phosphorylated and activated by RAF kinases (RAF1, BRAF, ARAF), these being activated by the small G protein RAS. The oncogenic nature of the pathway has resulted in the generation of highly specific inhibitors of the pathway that are successfully used to treat cancer, particularly melanoma. Those in clinical use currently inhibit some isoforms of RAS, RAF kinases and MEK1/2, with additional inhibitors of these kinases in clinical trials. New drugs are also entering the clinic to inhibit ERK1/2 themselves. The ERK1/2 cascade is also important in the heart. It promotes cardiomyocyte hypertrophy and cardioprotection to counter pathophysiological stresses, but plays a significant role in enhancing cardiac fibrosis with detrimental consequences for cardiac function. Here, we summarise the role of ERK1/2 signalling in cancer and the heart, we outline the development of ERK1/2 cascade inhibitors for cancer with information on those that are approved as cancer treatments and those in clinical trials, and discuss the known and predicted consequences of these ERK1/2 cascade inhibitors for the heart. Integral with this, we consider whether these drugs are necessarily detrimental to the heart or if/when they may be repurposed to prevent or treat heart failure.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/116609
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Biological Sciences > Biomedical Sciences
Publisher	Scilight
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