Department of General and Visceral Surgery, Ulm University Hospital, Ulm 89081, Germany.
World J Gastroenterol. 2021 Aug 14;27(30):4963-4984. doi: 10.3748/wjg.v27.i30.4963.
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
胰腺癌是一种发病率高、存活率低的恶性疾病。为了提高胰腺癌患者的总体生存率，迫切需要新的治疗方法。蛋白激酶是几乎所有发育阶段的关键调节因子，它们维持着生理功能，但也参与了致病过程。丝裂原活化蛋白激酶中的 c-Jun N 端激酶（JNK）和 p38 激酶以及蛋白激酶 CK1 家族是对炎症和代谢应激、DNA 损伤等细胞应激做出适当反应的重要介质。在其生理作用中，它们负责调节细胞周期进程、细胞增殖和分化以及细胞凋亡。因此，在各种癌症类型中，包括胰腺癌，都发现了这些通路的失调。多年来，这些通路的药理学靶向一直是研究的热点。尽管早期研究由于缺乏特异性和脱靶效应而收效甚微，但近年来针对应激激活蛋白激酶的小分子抑制剂设计及其联合治疗的应用的改进已经显示出了有希望的结果。因此，针对 JNK、p38 和 CK1 蛋白激酶家族成员的靶向治疗实际上可能在与这些激酶相关的高度失调激酶通路的精准医学领域具有特别的意义。然而，为了将应激激活激酶的抑制作用推进到转化医学领域，还需要进一步的研究，特别是涉及到探索和临床试验。
