文章：

细胞周期蛋白在癌症治疗中的前景

Cell cycle proteins as promising targets in cancer therapy

原文发布日期：2017-01-27

DOI: 10.1038/nrc.2016.138

类型: Review Article

开放获取: 否

要点：

1. Many cell cycle proteins are overexpressed or overactive in human cancers, in particular, D-type and E-type cyclins, cyclin-dependent kinases (CDK4, CDK6 and CDK2), Polo-like kinase 1 (PLK1) and Aurora kinases (Aurora A and Aurora B). In transgenic mice, overexpression of several of these cell cycle proteins induces or contributes to tumorigenesis, revealing their prominent oncogenic roles.
2. Some of these cell cycle proteins are also required for tumorigenesis, and their ablation in mice impairs tumour formation induced by specific genetic lesions or by carcinogen treatment, as demonstrated for several cyclins (D1, D2 and D3) and CDKs (CDK4, CDK6, CDK2 and CDK1), as well as for checkpoint kinase 1 (CHK1). Importantly, in some cases the continued presence of a cell cycle protein has also been shown to be required for tumour maintenance and progression, for example, for cyclin D1, cyclin D3 and CDK4, thereby providing a clear rationale for targeting these proteins in cancer treatment.
3. Kinases involved in cell cycle checkpoint function such as CHK1 and WEE1 also constitute potential therapeutic targets. Their inhibition compromises checkpoint function, causes excessive DNA damage and eventually leads to apoptosis, particularly in cells with compromised p53 function.
4. CDK4/6-selective inhibitors, such as palbociclib, ribociclib and abemaciclib, have shown significant benefits in clinical studies, particularly in breast cancer, but also in non-small-cell lung cancer, melanoma and head and neck squamous cell carcinoma. Importantly, following demonstration of a substantial improvement in progression-free survival, combination of palbociclib and letrozole received accelerated approval for first-line treatment of patients with advanced ER⁺HER2⁻ breast cancer.
5. Inhibitors of PLK1, such as rigosertib and volasertib, have also shown encouraging results in clinical phase II/III studies for patients with myelodysplastic syndromes and acute myelogenous leukaemia, respectively, and several phase III trials are currently ongoing.
6. Compounds targeting Aurora A, particularly alisertib, have been extensively studied in preclinical models and demonstrated synergy with many other targeted therapies, leading to tumour regression in various cancer models. Moreover, clinical studies revealed encouraging activity of alisertib in peripheral T cell lymphoma, non-Hodgkin lymphoma, non-small-cell lung cancer and breast cancer.

要点翻译：

1. 许多细胞周期蛋白在人类癌症中过度表达或过度活跃，特别是D型和E型细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK4、CDK6和CDK2）、Polo样激酶1（PLK1）和极光激酶（极光激酶A和极光激酶B）。在转基因小鼠中，这些细胞周期蛋白中几种的过度表达会诱导或促进肿瘤发生，揭示了它们显著的致癌作用。
2. 这些细胞周期蛋白中的一些也是肿瘤发生所必需的，并且它们在小鼠中的缺失会损害由特定遗传病变或致癌物处理诱导的肿瘤形成，如几种细胞周期蛋白（D1、D2和D3）和CDKs（CDK4、CDK6、CDK2和CDK1）以及检查点激酶1（CHK1）所证明的那样。重要的是，在某些情况下，细胞周期蛋白的持续存在也被证明是肿瘤维持和进展所必需的，例如细胞周期蛋白D1、细胞周期蛋白D3和CDK4，从而为在癌症治疗中靶向这些蛋白提供了明确的理由。
3. 参与细胞周期检查点功能的激酶，如CHK1和WEE1，也构成了潜在的治疗靶点。抑制这些激酶会损害检查点功能，导致过度的DNA损伤，并最终导致细胞凋亡，特别是在p53功能受损的细胞中。
4. CDK4/6选择性抑制剂，如palbociclib、ribociclib和abemaciclib，在临床研究中显示出显著的益处，特别是在乳腺癌中，而且在非小细胞肺癌、黑色素瘤和头颈部鳞状细胞癌中也是如此。重要的是，在证明无进展生存期有显著改善后，palbociclib和letrozole的联合疗法获得了加速批准，用于晚期ER+HER2−乳腺癌患者的一线治疗。
5. PLK1的抑制剂，如rigosertib和volasertib，在骨髓增生异常综合征和急性髓系白血病患者的临床II/III期研究中也显示出令人鼓舞的结果，并且目前有几项III期试验正在进行中。
6. 靶向极光激酶A的化合物，特别是alisertib，已在临床前模型中进行了广泛研究，并证明与许多其他靶向疗法有协同作用，导致在各种癌症模型中肿瘤消退。此外，临床研究显示alisertib在外周T细胞淋巴瘤、非霍奇金淋巴瘤、非小细胞肺癌和乳腺癌中具有令人鼓舞的活性。

英文摘要：

Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

摘要翻译： 

癌症的特征是肿瘤细胞不受控制的增殖，这是由于多种细胞周期蛋白的异常活性所致。因此，细胞周期调控因子被视为癌症治疗中有吸引力的靶点。有趣的是，动物模型表明，其中一些蛋白对于非转化细胞的增殖以及大多数组织的发育并非必需。相比之下，许多癌症却独特地依赖于这些蛋白，因此对其抑制具有选择性敏感性。经过数十年来对细胞周期蛋白的生理功能及其与癌症相关性的研究，这一认识最近转化为首个获批的靶向细胞周期直接调控因子的癌症治疗药物。在本综述中，我们重点关注直接调控细胞周期进程的蛋白（如细胞周期蛋白依赖性激酶（CDKs）），以及检查点激酶、极光激酶和Polo样激酶（PLKs）。我们讨论了细胞周期蛋白在癌症中的作用、在癌症治疗中靶向它们的理论基础以及临床试验结果，还探讨了各种细胞周期抑制剂的未来治疗潜力。

原文链接：

Cell cycle proteins as promising targets in cancer therapy