The history and future of targeting cyclin-dependent kinases in cancer therapy.
The history and future of targeting cyclin-dependent kinases in cancer therapy.
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靶向细胞周期蛋白依赖性激酶在癌症治疗中的历史和未来。
DOI：
10.1038/nrd4504
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发表时间：
2015-02
影响因子：
120.1
通讯作者：
Knudsen, Erik S.
中科院分区：
文献类型：
--
作者：
Asghar, Uzma;Witkiewicz, Agnieszka K.;Turner, Nicholas C.;Knudsen, Erik S.
癌症代表了不受控制的细胞分裂的病理表现;因此，长期以来，人们一直期望我们对细胞周期控制基本原理的理解将导致有效的癌症治疗。特别是，促进细胞周期转换的细胞周期蛋白依赖性激酶（CDK）预计将成为关键的治疗靶点，因为许多致瘤事件最终通过冲击细胞周期G1期的CDK 4或CDK 6复合物来驱动增殖。此外，CDK 2和CDK 1介导的染色体稳定性和S期和G2/M期控制方面的扰动是关键的致瘤事件。将这些知识转化为CDK抑制剂的成功临床开发历来具有挑战性，许多CDK抑制剂在临床试验中表现出令人失望的结果。在这里，我们回顾了CDK的生物学，治疗靶向离散激酶复合物的基本原理和CDK抑制剂的历史临床结果。我们还讨论了如何CDK抑制剂具有高选择性（特别是CDK 4和CDK 6），结合患者分层，导致更实质性的临床活性。
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.
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影响因子：
64.8
作者：
Bartkova, Jirina;Rezaei, Nousin;Gorgoulis, Vassilis G.
通讯作者：
Gorgoulis, Vassilis G.
影响因子：
64.5
作者：
Burd CE;Sorrentino JA;Clark KS;Darr DB;Krishnamurthy J;Deal AM;Bardeesy N;Castrillon DH;Beach DH;Sharpless NE
通讯作者：
Sharpless NE
影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
28.2
作者：
Aarts, Marieke;Sharpe, Rachel;Turner, Nicholas C.
通讯作者：
Turner, Nicholas C.
影响因子：
11.2
作者：
Bayart, E;Grigorieva, O;Amor-Guéret, M
通讯作者：
Amor-Guéret, M