CDK4 – a master regulator of the cell cycle

The mammalian cell cycle can be divided into four stages, namely Gap 1 (G1 stage), Synthesis (S stage), Gap 2 (G2 stage), and Mitosis (M stage). Its sequence and time are crucial for the accurate transmission of genetic information. Therefore, some biochemical pathways have evolved to ensure that the initiation of a specific cell cycle event depends on the accurate completion of another event. These biochemical pathways are called “checkpoints”.

 

The cell cycle is partially regulated by cyclins and their related serine/threonine cyclin-dependent kinases (CDKs). When CDK4 is combined with D-type cyclin, it will mediate the progress of the G1 phase when cells accurately start DNA synthesis. Although the mutant mice with Cdk4 deletion can survive, and cell proliferation will not be significantly affected in vitro due to the compensation role played by other CDKs, this gene plays a key role in mammalian development and carcinogenesis.

 

 

In a review article entitled “CDK4: a master regulator of the cell cycle and its role in cancer” published in the journal Genes & Cancer, scientists from Mount Sinai Icahn Medical College and other institutions discussed the key role of CDK4 in the cell cycle control, normal development, and tumorigenesis, as well as the status and effectiveness of approved small molecule CDK4/6 inhibitors for cancer therapy.

 

The researchers pointed out that CDK4/6 can act as a key mediator for cell cycle progression to the G1 phase, and the G1 phase is a critical period for cells to prepare to start DNA synthesis. Cells rely on this protein, its cyclin D binding chaperone, and downstream target RB to proliferate, which highlights the reason why CDK4/CYCLIN D/RB signal modules usually exhibit dysfunctions in transformed cells.

 

At present, three CDK4/6 inhibitors have been approved as new therapies for ER breast cancer, which paves the way for the clinical trials being carried out by scientists. These clinical studies aim to use these inhibitors in combination with other inhibitors of multiple signal pathways (such as but not only BRAF, PI3K, and MEK) to treat multiple types of tumors. These tumor types show dependence on CYCLIN D1/CDK4/RB or other cell cycle components (such as p16 and p27).

 

The success of these clinical trials and scientists’ understanding of the mechanisms that drive cancer cells to tolerate these inhibitors may help answer whether the selective inhibitors of CDK4/6 can provide certain therapeutic benefits for a wider range of cancers. To sum up, this review article discussed the key role of CDK4 in cell cycle control, normal development, and tumorigenesis, and the researchers also analyzed the current status of approved small molecule CDK4/6 inhibitors as cancer therapies.

 

Reference

Stacey J. Baker,Poulikos I. Poulikakos,Hanna Y. Irie, et al. CDK4: a master regulator of the cell cycle and its role in cancer, Genes & Cancer (2022). DOI:10.18632/genesandcancer.221