Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy.

Alessandro Tubita,Elisabetta Rovida,Ignazia Tusa

doi:10.3389/fcell.2021.647311

Alessandro Tubita, Elisabetta Rovida + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2021.647311

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Abstract

Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.

Highlights

The Mitogen-Activated Protein Kinase (MAPK) cascades are involved in a number of physiological processes and are activated by a large variety of stimuli
Regarding the MAPK cascade culminating in extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation, a variety of mitogens activate receptor tyrosine kinases (RTKs) or G-protein-coupled receptors that, in turn, activate the small GTPase RAS proteins (K-RAS, H-RAS, or N-RAS) that are responsible for the recruitment of RAF kinases
We describe the accumulating lines of evidence pointing to ERK5 activation as a compensatory mechanism occurring upon RAF-MEK1/2-ERK1/2 inhibition, and determining de facto the resistance to therapeutic strategies based on this inhibition

Summary

INTRODUCTION

The Mitogen-Activated Protein Kinase (MAPK) cascades are involved in a number of physiological processes and are activated by a large variety of stimuli. In keeping with a possible involvement of ERK5 in MAPKi resistance in N-RAS-mutated melanomas, a recent report showed that the treatment with MEK1/2i (Trametinib, Binimetinib, Selumetinib, or Cobimetinib) or ERK1/2i (GDC-0994; Robarge et al, 2014) determined a delayed activation of ERK5 through a PDGFRi-sensitive pathway (Adam et al, 2020). Combined MEK5-ERK5 co-targeting using Trametinib + XMD8-92 or Trametinib + ERK5 genetic inhibition (shRNA) prevented long-term growth in vitro, supporting the relevance of ERK5 in the proliferation and survival of N-RAS-mutated melanoma cells upon MEK1/2-ERK1/2 inhibition. ALK-addicted neuroblastoma cells treated with the MEK1/2i Trametinib showed an increased phosphorylation/activation of the AKT and ERK5 kinases, that the authors proposed to be responsible for a compensatory mechanism supporting cell proliferation. DUSPs prevented ERK5 phosphorylation, so that when MEK1/2ERK1/2 is inhibited DUSPs inactivation resulted in enhanced

Effective combined targeting strategies

Findings

AUTHOR CONTRIBUTIONS