CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought

Cancer Cell. 2018 Jul 9;34(1):9-20. doi: 10.1016/j.ccell.2018.03.023. Epub 2018 May 3.

Abstract

CDK4/6 inhibitors are among a new generation of therapeutics. Building upon the striking success of the combination of CDK4/6 inhibitors and the hormone receptor antagonist letrozole in breast cancer, many other combinations have recently entered clinical trials in multiple diseases. To achieve maximal benefit with CDK4/6 inhibitors it will be critical to understand the cellular mechanisms by which they act. Here we highlight the mechanisms by which CDK4/6 inhibitors can exert their anti-tumor activities beyond simply enforcing cytostatic growth arrest, and discuss how this knowledge may inform new combinations, improve outcomes, and modify dosing schedules in the future.

Keywords: CDK4/6 inhibitors; abemaciclib; metabolism; palbociclib; ribociclib; senescence; tumor microenvironment.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Cycle Checkpoints / drug effects*
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Drug Design*
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / therapeutic use*
  • Signal Transduction

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6