CDK6—the Hot Potato in Cancer Treatment

It is well known that the formation of tumors is a multi-step process in which cells acquire genetic and epigenetic changes during tumorigenesis and eventually reach a state of complete transformation. The cell cycle kinase CDK6 has received a lot of attention in the past few years. It is not only a cell cycle-dependent kinase but also a transcriptional regulator with functional characteristics different from the same family of CDK4. CDK6 regulates the expression of many genes, and some studies have found that this molecule can promote the development of malignant blood diseases such as AML and ALL, and is also important for the self-sustaining of hematopoietic stem cells and leukemia stem cells.

Recently, researchers from Vienna reported that CDK6 is able to antagonize p53-induced responses. Previous studies have found that high and low expression of CDK6 are associated with poor prognosis, but the reasons for this have not been revealed. In this study, the researchers found that CDK6 promotes tumor formation by regulating transcriptional responses at specific stages. In the early stages of tumorigenesis, CDK6 kinase prevents p53 from acting in hematopoietic cells by inducing a complex transcriptional program. Cells lacking CDK6 kinase function require the presence of TP53 mutations to achieve a fully transformed immortal state.

The researchers found that CDK6 binds to promoters of many genes, including p53 antagonists Prmt5, Ppm1d and Mdm4. The researchers said the findings of the study were also confirmed in patients: the frequency of TP53 mutations in tumors expressing low levels of CDK6 was higher than expected. The study found that CDK6 can promote cell cycle progression to antagonize stress responses and affect the effects of p53 and RB. Specific inhibition of CDK6 kinase activity results in cells more susceptible to p53-induced cell death and also stimulates the growth of p53 mutant clones in precancerous cells.