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.

自细胞外信号调节激酶5（ERK5）及其上游激活剂有丝分裂原激活的蛋白激酶5（MEK5）首次出现以来，已经过去了20年。尽管我们在确定失调的MEK5-ERK5信号转导与上皮和非上皮恶性肿瘤发病机制之间的联系上已经走了很长一段路，但是选择性靶向这种独特途径仍然难以捉摸。在这里，我们提供了现有证据的最新综述，这些证据表明异常的MEK5-ERK5（磷酸）蛋白质组/转录组谱，激进的癌症状态和患者预后不良之间存在相关性。然后，我们集中于临床前模型中有关ERK5活性上调与促进肿瘤生长，转移，治疗耐药性，未分化性状和免疫抑制的相关性的新见解，