Chapter Four - Cyclin D-CDK4/6 functions in cancer

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Abstract

The mammalian cell cycle is driven by a complex of cyclins and their associated cyclin-dependent kinases (CDKs). Abnormal dysregulation of cyclin-CDK is a hallmark of cancer. D-type cyclins and their associated CDKs (CDK4 and CDK6) are key components of cell cycle machinery in driving G1 to S phase transition via phosphorylating and inactivating the retinoblastoma protein (RB). A body of evidence shows that the cyclin Ds-CDKs axis plays a critical role in cancer through various aspects, such as control of proliferation, senescence, migration, apoptosis, and angiogenesis. CDK4/6 dual-inhibitors show significant efficacy in pre-clinical or clinical cancer therapies either as single agents or in combination with hormone, chemotherapy, irradiation or immune treatments. Of note, as the associated partner of D-type cyclins, CDK6 shows multiple distinct functions from CDK4 in cancer. Depletion of the individual CDK may provide a therapeutic strategy for patients with cancer.

Section snippets

Canonical functions of cyclin Ds-CDK4/6

Uncontrolled cell proliferation is a hallmark of cancer where cell cycle progression is deregulated (Hanahan & Weinberg, 2011). There are four phases of the mitotic cell division cycle, i.e., mitosis (M), the cellular DNA synthesis (S) phase, the first gap phase (G1) between M and S phases, and the second gap phase (G2) between S and M phases. As the important cell cycle machineries, cyclins (A, B, D, and E) and their associated cyclin-dependent kinases (CDKs 1, 2, 4, and 6) are critical in

Cyclin Ds-CDK4/6 in tumor microenvironment cells

As a critical component of solid tumors, the tumor microenvironment, including the surrounding blood vessels, immune cells, stromal cells/fibroblasts and extracellular matrix, plays a significant role in regulating tumorigenesis. Emerging roles of cyclin D-CDKs in tumor microenvironment cells have been reported, in addition to their essential roles in tumor cells.

Tumor-associated macrophages, the most abundant immune cell population in tumor tissue, enhance tumor malignant progression as well

CDK4/6 as therapeutic targets for cancer treatments

The significant roles of cyclin D-CDK4/6 in cancer cells contributing to tumor progression have been well studied, which has led to clinical applications of CDK4/6 dual-inhibitors in multiple types of cancers. The first non-specific CDK inhibitors were generated around 30 years ago with the identification of CDKs as the key drivers for cell cycle transitions. Nowadays, these pan-inhibitors have been replaced with more specific CDK4/6 dual-inhibitors, partially due to their dose-limiting

The distinct functional aspects of CDK6 from CDK4 and perspectives

Human cells have 20 CDKs, and CDKs are traditionally grouped into three cell cycle or five transcriptional subfamilies (Cao et al., 2014; Malumbres, 2014). CDK4 and CDK6 are homologous proteins and carry out cell cycle functions through phosphorylating and inactivating downstream RB proteins at their serine/threonine residues. Although CDK4 and CDK6 associated with cyclin Ds have similar cell cycle regulatory function, increasing evidence shows distinct biological functions between CDK4 and

Future perspectives on controlling CDK activities

Though increasing evidence show that CDK4 and CDK6 carry out distinct functions in the progression of different types of tumors, to our knowledge, no published kinase inhibitor can specifically discriminate between CDK6 and CDK4. It is likely due to the high amino acid sequence identify (94%) in their ATP-binding pockets. Moreover, both CDK6 and CDK4 possess kinase independent functions in tumor progression, and inhibiting the kinase activity of CDK4/6 alone cannot prevent their kinase

Acknowledgments

This work was supported by National Institute of General Medical Sciences, National Institutes of Health Institutional Developmental Award (COBRE) 5P20GM103542-08; Hollings Cancer Center Research Project-Swim Across America; and American Cancer Society Institutional Research Awards (ACS-IRG) IRG-19-137-20 to Haizhen Wang. We apologize to authors whose work did not be included due to space limitation.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed by authors.

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