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

Uzma Asghar, Agnieszka K. Witkiewicz, Nicholas C. Turner, Erik S. Knudsen

Research output: Contribution to journalArticle

501 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)130-146
Number of pages17
JournalNature Reviews Drug Discovery
Volume14
Issue number2
DOIs
StatePublished - Jan 1 2015

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Cyclin-Dependent Kinases
History
Neoplasms
Cell Cycle
Therapeutics
Chromosomal Instability
G1 Phase
Cell Cycle Checkpoints
S Phase
Cell Division
Phosphotransferases
Clinical Trials

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

The history and future of targeting cyclin-dependent kinases in cancer therapy. / Asghar, Uzma; Witkiewicz, Agnieszka K.; Turner, Nicholas C.; Knudsen, Erik S.

In: Nature Reviews Drug Discovery, Vol. 14, No. 2, 01.01.2015, p. 130-146.

Research output: Contribution to journalArticle

Asghar, Uzma ; Witkiewicz, Agnieszka K. ; Turner, Nicholas C. ; Knudsen, Erik S. / The history and future of targeting cyclin-dependent kinases in cancer therapy. In: Nature Reviews Drug Discovery. 2015 ; Vol. 14, No. 2. pp. 130-146.
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