Targeted Avenues for Cancer Treatment: The MEK5-ERK5 Signaling Pathway.

Twenty years have passed since extracellular signal-regulated kinase 5 (ERK5) and its upstream activator, mitogen-activated protein kinase 5 (MEK5), first emerged onto the cancer research scene. Although we have come a long way in defining the liaison between dysregulated MEK5-ERK5 signaling and the pathogenesis of epithelial and nonepithelial malignancies, selective targeting of this unique pathway remains elusive. Here, we provide an updated review of the existing evidence for a correlation between aberrant MEK5-ERK5 (phospho)proteomic/transcriptomic profiles, aggressive cancer states, and poor patient outcomes. We then focus on emerging insights from preclinical models regarding the relevance of upregulated ERK5 activity in promoting tumor growth, metastasis, therapy resistance, undifferentiated traits, and immunosuppression, highlighting the opportunities, prospects, and challenges of selectively blocking this cascade for antineoplastic treatment and chemosensitization.