Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health?

Review Inhibiting the Extracellular Signal-regulated Kinase 1/2 (ERK1/2) Cascade in Cancer and the Heart: for Better or Worse, in Sickness and Health? Angela Clerk *, Shona U Amadi, Samuel J Smith, and Peter H Sugden School of Biological Sciences, University of Reading, Reading RG6 6AS, UK * Correspondence: a.clerk@reading.ac.uk   Received: 3 April 2024; Revised: 27 April 2024; Accepted: 29 April 2024; Published: 23 May 2024   Abstract: 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 in turn phosphorylated and activated by RAF kinases (RAF1, BRAF, ARAF), these being activated by small G proteins of the RAS family (HRAS, KRAS, NRAS). The oncogenic nature of the pathway has resulted in the generation of highly specific inhibitors 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 now 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, and 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 providing information on those that are approved as cancer treatments and those which are in clinical trials, and we 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.