Treating cancer with selective CDK4/6 inhibitors

Nat Rev Clin Oncol. 2016 Jul;13(7):417-30. doi: 10.1038/nrclinonc.2016.26. Epub 2016 Mar 31.

Abstract

Uncontrolled cellular proliferation, mediated by dysregulation of the cell-cycle machinery and activation of cyclin-dependent kinases (CDKs) to promote cell-cycle progression, lies at the heart of cancer as a pathological process. Clinical implementation of first-generation, nonselective CDK inhibitors, designed to inhibit this proliferation, was originally hampered by the high risk of toxicity and lack of efficacy noted with these agents. The emergence of a new generation of selective CDK4/6 inhibitors, including ribociclib, abemaciclib and palbociclib, has enabled tumour types in which CDK4/6 has a pivotal role in the G1-to-S-phase cell-cycle transition to be targeted with improved effectiveness, and fewer adverse effects. Results of pivotal phase III trials investigating palbociclib in patients with advanced-stage oestrogen receptor (ER)-positive breast cancer have demonstrated a substantial improvement in progression-free survival, with a well-tolerated toxicity profile. Mechanisms of acquired resistance to CDK4/6 inhibitors are beginning to emerge that, although unwelcome, might enable rational post-CDK4/6 inhibitor therapeutic strategies to be identified. Extending the use of CDK4/6 inhibitors beyond ER-positive breast cancer is challenging, and will likely require biomarkers that are predictive of a response, and the use of combination therapies in order to optimize CDK4/6 targeting.

Publication types

  • Review

MeSH terms

  • Aminopyridines / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Benzimidazoles / therapeutic use
  • Breast Neoplasms / drug therapy*
  • Cell Cycle / drug effects
  • Clinical Trials as Topic
  • Cyclin D1 / antagonists & inhibitors
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Female
  • Forecasting
  • Humans
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy*
  • Piperazines / therapeutic use
  • Purines / therapeutic use
  • Pyridines / therapeutic use

Substances

  • Aminopyridines
  • Benzimidazoles
  • Piperazines
  • Purines
  • Pyridines
  • Cyclin D1
  • abemaciclib
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • palbociclib
  • ribociclib