Format

Send to

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

The history and future of targeting cyclin-dependent kinases in cancer therapy.

Author information

1
Breakthrough Breast Cancer Research Centre, Chester Beatty Laboratories, Institute of Cancer Research, London, SW3 6JB, UK.
2
Simmons Cancer Center and Department of Pathology, University of Texas Southwestern, Dallas, USA.
3
Institute of Cancer Research and Royal Marsden NHS Foundation Trust Breast Cancer Unit, London, SW3 6JJ, UK.

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.

PMID:
25633797
PMCID:
PMC4480421
DOI:
10.1038/nrd4504
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center