Abstract
Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.
Highlights
Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation
While cyclin-dependent kinases (CDKs) activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells
It consists of four phases: gap 1 (G1), where the cell grows in size and transcribes the RNA and protein necessary during cell division; synthesis or S phase, where all chromosomes are being replicated; gap 2 (G2), where cell growth and protein synthesis continue; and mitosis or M phase, where the cell restructures its membrane and organizes the newly synthesized chromosomes and divides into two daughter cells
Summary
Transition from quiescence or G0 phase in G1 phase is modulated by growth factor signals or mitogenic stimulation. CDK5 upregulation is mostly observed in, but not limited to, neurons, and is often correlated to cell apoptosis It can regulate the cell cycle by phosphorylating Rb and interacting with E2F during G1 phase (Zhang et al, 2010; Chang et al, 2012; Futatsugi et al, 2012). Abundant levels of CDK4 are especially observed in CRC patients with enhanced dysplasia and are correlated to increased tumor cell proliferation (Zhang et al, 1997; Bartkova et al, 2001). CDK5 expression is reported to be much higher in CRC cells compared to normal epithelium and it correlates to increased tumor growth and poor prognosis (Zhuang et al, 2016; de Porras et al, 2019).
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