The History and Future of Targeting Cyclin-Dependent Kinases in Cancer Therapy

Nat Rev Drug Discov. 2015 Feb;14(2):130-46. doi: 10.1038/nrd4504.

Abstract

Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Cycle / drug effects
  • Clinical Trials as Topic
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Molecular Structure
  • Molecular Targeted Therapy* / methods
  • Molecular Targeted Therapy* / trends
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / pathology
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Cyclin-Dependent Kinases