The Emerging Role of Cyclin-Dependent Kinases (CDKs) in Pancreatic Ductal Adenocarcinoma

Abstract

The family of cyclin-dependent kinases (CDKs) has critical functions in cell cycle regulation and controlling of transcriptional elongation. Moreover, dysregulated CDKs have been linked to cancer initiation and progression. Pharmacological CDK inhibition has recently emerged as a novel and promising approach in cancer therapy. This idea is of particular interest to combat pancreatic ductal adenocarcinoma (PDAC), a cancer entity with a dismal prognosis which is owed mainly to PDAC's resistance to conventional therapies. Here, we review the current knowledge of CDK biology, its role in cancer and the therapeutic potential to target CDKs as a novel treatment strategy for PDAC.

Keywords: CDK; cyclin-dependent kinase; pancreatic cancer; pancreatic ductal adenocarcinoma.

Figure 1

The cell cycle phases and their associated cyclin-dependent kinases (CDK)/cyclin complexes. In the G1 phase of the cell cycle, the synthesis of cyclin D is increased. This cyclin partners with CDK4/6 to promote cell cycle entry, and its progression through G1, as well as the G1/S transition. During the S phase, CDK2 in complex with cyclin A controls the phosphorylation of targets involved in DNA replication. Cyclin A is found highly expressed in this phase and until the last stages of G2. In the G2 phase, the primary regulator of the cell cycle is CDK1.

Figure 2

Transcription and its associated CDK/cyclin complexes. RNA Pol II forms part of the pre-initiation complex that starts gene transcription in eukaryotes. This pre-initiation complex is inhibited by the Mediator complex, of which CDK8 and cyclin C are part. The Mediator complex represses transcription by phosphorylating the C-terminal domain (CTD) of RNA Pol II to prevent its recruitment to the promoter and by phosphorylating cyclin H. Cyclin H in complex with CDK7 forms part of the transcription factor complex TFIIH, which in turn phosphorylates the CTD of RNA Pol II, triggering the transition from transcription initiation to mRNA elongation. TFIIH phosphorylates cyclin T as well. The CDK9/cyclin T complex forms part of the positive transcription elongation factor b (pTEFb), which phosphorylates the RNA Pol II CTD, thus promoting the extension of the pre-mRNA.