Abstract
Simple SummaryPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans, due to late diagnosis and limited treatment possibilities. Improved treatment for PDAC patients is warranted. Cyclin-dependent kinase 1 (CDK1) is a stimulator of cell cycle progression and its activity is regularly enhanced in pancreatic cancer cells. Therefore, CDK1 has been proposed as a novel drug target to treat patients with PDAC. This review describes the potential of CDK1 inhibition as a treatment for PDAC by outlining the molecular pathways influenced by CDK1 inhibition and new therapeutic strategies.The role of CDK1 in PDAC onset and development is two-fold. Firstly, since CDK1 activity regulates the G2/M cell cycle checkpoint, overexpression of CDK1 can lead to progression into mitosis even in cells with DNA damage, a potentially tumorigenic process. Secondly, CDK1 overexpression leads to the stimulation of a range of proteins that induce stem cell properties, which can contribute to the development of cancer stem cells (CSCs). CSCs promote tumor-initiation and metastasis and play a crucial role in the development of PDAC. Targeting CDK1 showed promising results for PDAC treatment in different preclinical models, where CDK1 inhibition induced cell cycle arrest in the G2/M phase and led to induction of apoptosis. Next to this, PDAC CSCs are uniquely sensitive to CDK1 inhibition. In addition, targeting of CDK1 has shown potential for combination therapy with both ionizing radiation treatment and conventional chemotherapy, through sensitizing tumor cells and reducing resistance to these treatments. To conclude, CDK1 inhibition induces G2/M cell cycle arrest, stimulates apoptosis, and specifically targets CSCs, which makes it a promising treatment for PDAC. Screening of patients for CDK1 overexpression and further research into combination treatments is essential for optimizing this novel targeted therapy.
Highlights
With a 5-year survival rate of only 10 percent, pancreatic cancer is one of the most lethal cancers in humans [1]
cyclin-dependent kinase 1 (CDK1) genes are significantly overexpressed in tumor cells of Pancreatic ductal adenocarcinoma (PDAC) patients [14], which is associated with more advanced stages of PDAC and is an indicator of poor survival rates for patients
Another study showed that treatment of human pancreatic cancer cell lines with the HDAC inhibitor TSA and the flavonoid silibinin led to a downregulation of Bcl-xL, which was accompanied by inhibition of CDK1 [36]
Summary
With a 5-year survival rate of only 10 percent, pancreatic cancer is one of the most lethal cancers in humans [1]. CDK1 genes are significantly overexpressed in tumor cells of PDAC patients [14], which is associated with more advanced stages of PDAC and is an indicator of poor survival rates for patients. Inhibition of CDC25, an activator of CDK1, leads to a reduction in growth of pancreatic cancer cell lines [15]. Together, these studies indicate the potential of CDK1 inhibition as a novel drug target to treat PDAC. Several other studies indicate the potential of CDK1 inhibition for both cancer treatment in general [16,17], and for PDAC [18,19]. Cancers 2021, 13, 4389 inhibitor would influence the molecular pathways involved in PDAC to exert its proposed anticancer mechanism
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