Cyclin D-CDK4/6 functions in cancer

Adv Cancer Res. 2020:148:147-169. doi: 10.1016/bs.acr.2020.02.002. Epub 2020 Apr 2.

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.

Keywords: Abemaciclib; CDK4; CDK4/6 inhibitor; CDK6; Cyclin; Cyclin-dependent kinases; PROTAC; Palbociclib; RB; Ribociclib.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cyclin D / antagonists & inhibitors*
  • Cyclin D / metabolism
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*

Substances

  • Cyclin D
  • Protein Kinase Inhibitors
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6