Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
Trends Mol Med. 2020 Apr;26(4):394-407. doi: 10.1016/j.molmed.2020.01.006. Epub 2020 Feb 13.
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.
ERK5 和其上游激活剂 MAPK5（MEK5）首次出现在癌症研究领域已经过去了 20 年。尽管我们已经在定义失调的 MEK5-ERK5 信号与上皮和非上皮恶性肿瘤发病机制之间的联系方面取得了很大进展，但对该独特途径的选择性靶向仍然难以捉摸。在这里，我们提供了对异常 MEK5-ERK5（磷酸化）蛋白组/转录组谱与侵袭性癌症状态和不良患者预后之间相关性的最新综述。然后，我们专注于临床前模型中关于上调的 ERK5 活性在促进肿瘤生长、转移、治疗耐药性、未分化特征和免疫抑制方面的相关性的新见解，强调了选择性阻断这一级联反应用于抗肿瘤治疗和化疗增敏的机会、前景和挑战。
