Stress-activated kinases as therapeutic targets in pancreatic cancer

Abstract

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 in vitro 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 in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.

Keywords: Pancreatic cancer; Stress-activated protein kinases; Mitogen-activated protein kinases; c-Jun N-terminal kinases; Casein kinase 1; Small molecule inhibitor

Core Tip: Since pancreatic cancer patients are generally confronted with poor prognosis, optimized therapeutic strategies are urgently needed. To establish new treatment options, efforts in drug development have increasingly focused on targeting protein kinases. In the cellular response to various stress signals, c-Jun N-terminal kinases (JNK) and p38 kinases as well as members of the casein kinase 1 (CK1) family are of special interest. Concentrating on pancreatic carcinoma in this review, we summarize the key roles of JNK, p38, and CK1 and provide an overview of recent achievements in the development of small molecule kinase inhibitors against these kinases.