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

Figure 1

Signal integration mediated by stress-activated protein kinases. The stress-activated protein kinases (SAPKs) c-Jun N-terminal kinase (JNK) and p38 as well as the protein kinases of the casein kinase 1 (CK1) family are activated in response to endogenous and exogenous stress stimuli. Therefore, JNK and p38 are either activated directly or through upstream signaling cascades [mitogen-associated protein kinase kinase kinases (MKKKs), mitogen-associated protein kinase kinases (MKKs)] and subsequently exercise their functions through intracellular signal integrating effectors such as the transcription factors JNK, p53, c-myc, or β-catenin. In response to certain stress stimuli, the kinases of the CK1 family also take key functions in regulatory effects mediated via p53 or through various signal transduction pathways like the Wnt/β-catenin, Hedgehog (Hh), or Hippo pathway. Finally, cellular stress response including regulation of proliferation, differentiation, migration, cell cycle progression, survival, and apoptosis is initiated by modulation of gene expression. MAP: Microtubule-associated protein; MMP: matrix metalloproteinase; MT: Microtubule; ROS: Reactive oxygen species.