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Cyclin D as a therapeutic target in cancer

Key Points

  • Cyclin D–cyclin-dependent kinase 4 (CDK4) or CDK6 activation promotes cell cycle progression through the phosphorylation of substrates, including RB and transcription factors with roles in proliferation and differentiation. These kinase complexes also target substrates with roles in centrosome duplication, mitochondrial function, cell growth, cell adhesion and motility, and cytoskeletal modelling.

  • D-type cyclins have non-catalytic roles in which interactions with chromatin-modifying enzymes and diverse transcription factors, including steroid hormone receptors, leads to the transcriptional regulation of suites of genes that are involved in proliferation and differentiation. Independently of CDK activation, the D-type cyclins also facilitate efficient DNA repair and indirectly activate CDK2 through the sequestration of CDK inhibitors.

  • CCND1 is an established human oncogene that is commonly overexpressed through copy number alterations, or more rarely by mutation, or as a consequence of the deregulation of mitogenic signalling downstream of oncogenes such as ERBB2. CCND1 overexpression causes a number of potentially oncogenic responses in experimental models and is associated with poor patient outcome.

  • Cyclin D1 and its associated CDKs are potential therapeutic targets. Promising results from early CDK inhibitors in experimental systems were not followed by evidence for efficacy in clinical trials. Possible reasons for this disappointing outcome include poor pharmacokinetics, suboptimal dosing schedules and clinical testing in unselected patient populations. Second-generation, more selective inhibitors of CDK4 and CDK6 are now undergoing clinical testing.

  • Possible alternative approaches to targeting cyclin D1 include the use of compounds that affect CCND1 transcription or cyclin D1 protein turnover, and the use of combination therapies that simultaneously target multiple end points of cyclin D1 action. Central to the effective use of these novel approaches is the better selection of patient subgroups that are likely to respond.

Abstract

Cyclin D1, and to a lesser extent the other D-type cyclins, is frequently deregulated in cancer and is a biomarker of cancer phenotype and disease progression. The ability of these cyclins to activate the cyclin-dependent kinases (CDKs) CDK4 and CDK6 is the most extensively documented mechanism for their oncogenic actions and provides an attractive therapeutic target. Is this an effective means of targeting the cyclin D oncogenes, and how might the patient subgroups that are most likely to benefit be identified?

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Figure 1: CDK-dependent functions of cyclin D.
Figure 2: CDK-independent functions of cyclin D1.
Figure 3: Oncogenic activation of cyclin D1.
Figure 4: Therapeutic targeting of cyclin D1.

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Acknowledgements

The authors are grateful to C. M. McNeil and C. M. Sergio for assistance with literature searches, A. V. Biankin for thought-provoking discussions and I. Rooman for helpful comments. The authors' research is supported by the National Health and Medical Research Council of Australia, Cancer Institute New South Wales, National Breast Cancer Foundation, Cure Cancer Australia Foundation, the Australian Cancer Research Foundation, the Petre Foundation, Young Garvan and the RT Hall Trust.

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Glossary

INK4 family

This family of CDK inhibitor proteins specifically prevent the activation of CDK4 and CDK6, generally by inhibiting cyclin D association.

CIP and KIP family

This family of CDK inhibitor proteins bind cyclin–CDK complexes and are potent inhibitors of cyclin E–CDK2 and cyclin A–CDK2. They act as assembly factors for cyclin D–CDK4 and cyclin D–CDK6, but can also inhibit the activity of these kinases.

DNA damage response

A global cellular response that halts cell cycle progression while damaged DNA is repaired, or that triggers cell death by apoptosis if the damage is too extensive for repair.

Cyclin box

A domain that is characteristic of cyclins and has high sequence conservation across the cyclin family. It mediates cyclin–CDK binding.

Oncogene addiction

Heightened dependency of cancer cells on specific oncogenes, so that, despite the presence of multiple genomic alterations, inactivation of a single oncogene can be sufficient to impair proliferation and survival.

Phase I and II clinical trials

The first stages of clinical testing in humans. Phase I trials include tests of safety, tolerability, and pharmacokinetics; Phase II trials begin to assess efficacy.

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Musgrove, E., Caldon, C., Barraclough, J. et al. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer 11, 558–572 (2011). https://doi.org/10.1038/nrc3090

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