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. Is the ability of D-type cyclins to activate cyclin-dependent kinases an effective means of targeting these oncogenes, and how might the patient subgroups that are most likely to benefit be identified? 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 kin