文章：

细胞周期蛋白D作为癌症的治疗靶点

Cyclin D as a therapeutic target in cancer

原文发布日期：2011-06-09

DOI: 10.1038/nrc3090

类型: Review Article

开放获取: 否

要点：

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

要点翻译：

1. 细胞周期蛋白D-细胞周期蛋白依赖性激酶4（CDK4）或CDK6的激活通过磷酸化底物（包括RB及参与增殖和分化的转录因子）来促进细胞周期进程。这些激酶复合物还靶向参与中心体复制、线粒体功能、细胞生长、细胞粘附与运动以及细胞骨架建模的底物。
2. D型细胞周期蛋白具有非催化作用，通过与染色质修饰酶和多种转录因子（包括类固醇激素受体）相互作用，导致参与增殖和分化的基因组的转录调控。独立于CDK激活，D型细胞周期蛋白还促进有效的DNA修复，并通过隔离CDK抑制剂间接激活CDK2。
3. CCND1是一种已确认的人类癌基因，通常通过拷贝数改变过表达，较少通过突变或由于ERBB2等癌基因下游有丝分裂信号失调而导致。在实验模型中，CCND1过表达引起许多潜在的致癌反应，并与患者不良预后相关。
4. 细胞周期蛋白D1及其相关CDK是潜在的治疗靶点。早期CDK抑制剂在实验系统中取得的令人鼓舞的结果并未在临床试验中获得疗效证据。导致这一 disappointing 结果的可能原因包括药代动力学差、给药方案欠佳以及在未筛选患者人群中进行临床测试。目前，第二代更具选择性的CDK4和CDK6抑制剂正在进行临床测试。
5. 靶向细胞周期蛋白D1的可能替代方法包括使用影响CCND1转录或细胞周期蛋白D1蛋白转换的化合物，以及使用同时靶向细胞周期蛋白D1作用多个终点的联合疗法。有效使用这些新方法的核心在于更好地筛选可能响应的患者亚组。

英文摘要：

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?

摘要翻译： 

Cyclin D1，以及在较小程度上其他D型细胞周期蛋白，在癌症中经常失调，是癌症表型和疾病进展的生物标志物。这些细胞周期蛋白激活细胞周期蛋白依赖性激酶（CDKs）CDK4和CDK6的能力是它们致癌作用最广泛记录的机制，并提供了一个有吸引力的治疗靶点。这是否是靶向细胞周期蛋白D致癌基因的有效手段，以及如何识别最有可能受益的患者亚群？

原文链接：

Cyclin D as a therapeutic target in cancer