CDK4 and CDK6 kinases: From basic science to cancer therapy.
CDK4 and CDK6 kinases: From basic science to cancer therapy.
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DOI：
10.1126/science.abc1495
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发表时间：
2022-01-14
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细胞周期蛋白依赖性激酶 4 和 6（CDK4 和 CDK6）及其激活伙伴 D 型细胞周期蛋白将细胞外环境与核心细胞周期机制联系起来。细胞周期蛋白 D-CDK4/6 的组成型激活代表了多种癌症类型中肿瘤发生的驱动力。 CDK4/6 的小分子抑制剂已在治疗激素受体阳性乳腺癌方面取得了巨大成功，并且正在进行许多其他肿瘤类型的临床试验。出乎意料的是，最近的研究表明，抑制CDK4/6会影响广泛的细胞功能，例如肿瘤细胞代谢或抗肿瘤免疫。在这篇综述中，我们讨论了了解 CDK4/6 生物学的最新进展如何为未来使用细胞周期蛋白 D-CDK4/6 抑制剂在癌症治疗中开辟新途径。在这篇评论中，Fassl 等人。讨论 CDK4 和 CDK6 激酶的基础生物学、导致将 CDK4/6 鉴定为优秀抗癌靶标的研究、CDK4/6 抑制剂在癌症治疗中的日益增长的应用以及这些化合物对未来治疗的前景。细胞周期蛋白和细胞周期蛋白依赖性激酶 (CDK) 驱动细胞分裂。对于癌症领域特别重要的是 D-细胞周期蛋白，它结合并激活 CDK4 和 CDK6。在正常细胞中，细胞周期蛋白 D-CDK4/6 的活性受细胞外促增殖或抑制信号控制。相比之下，在许多癌症中，细胞周期蛋白 D-CDK4/6 激酶过度激活并且变得独立于促有丝分裂刺激，从而驱动不受控制的肿瘤细胞增殖。小鼠基因实验证实，细胞周期蛋白 D-CDK4/6 激酶对于许多肿瘤类型的生长至关重要，并且它们代表了潜在的治疗靶点。遗传和细胞培养研究记录了乳腺癌细胞对 CDK4/6 的依赖性。在临床前研究中合成并测试了化学 CDK4/6 抑制剂。将这些化合物引入临床代表了乳腺癌治疗的突破，并可能对许多其他肿瘤类型的治疗产生重大影响。小分子 CDK4/6 抑制剂（palbociclib、ribociclib 和 abemaciclib）在针对激素受体阳性乳腺癌患者的临床试验中显示出令人印象深刻的结果。在标准内分泌治疗中添加 CDK4/6 抑制剂可显着延长中位无进展生存期，并延长中位总生存期。因此，所有三种 CDK4/6 抑制剂都获得了美国食品和药物管理局的“突破性疗法”认定，并已被批准用于治疗患有晚期/转移性激素受体阳性乳腺癌的女性。在过去的几年中，人们对基本 CDK4/6 生物学的重新兴趣产生了一些令人惊讶的发现。新出现的概念是 CDK4/6 激酶调节的细胞功能比之前预期的要广泛得多。因此，CDK4/6 抑制剂除了抑制肿瘤细胞增殖外，还通过刚刚开始阐明的机制影响肿瘤细胞和肿瘤环境。例如，抑制 CDK4/6 会影响作用于肿瘤细胞和宿主免疫系统的抗肿瘤免疫。重要的是，CDK4/6 抑制剂被证明可以大大增强临床前小鼠癌症模型中免疫检查点阻断的功效。这些新概念目前正在临床试验中进行测试。 Palbociclib、ribociclib 和 abemaciclib 目前正在 300 多个活跃或招募的临床试验中进行测试，涉及 50 多种肿瘤类型，例如乳腺癌的其他亚型（HER2 阳性、三阴性），以及结肠癌、肺癌、肝癌、子宫癌和卵巢癌、胶质母细胞瘤和各种淋巴恶性肿瘤。这些试验测试 CDK4/6 抑制剂与多种针对其他癌症相关途径的治疗化合物的组合。其他几种联合疗法在临床前研究中被证明是有效的，并将在不久的将来进入临床试验。另一种 CDK4/6 抑制剂 trilaciclib 正在测试其保护宿主正常非转化细胞免受化疗细胞毒性作用的能力。新的 CDK4/6 抑制剂已经开发出来，并正在临床前和临床试验中进行测试。 CDK4/6抑制剂治疗应用的主要障碍是最初对治疗有反应的患者通常会产生耐药性并最终死于该疾病。此外，相当一部分肿瘤表现出对 CDK4/6 抑制剂预先存在的内在耐药性。主要挑战之一是阐明全方位的耐药分子机制。即使目前的知识有限，人们也可以设想新的、改进的方法的原理，以克服已知的阻力机制。另一个尚未探索的领域是 CDK4/6 可能参与癌症以外的其他病理状态。该领域将成为深入研究的主题，并且可能将 CDK4/6 抑制剂的用途扩展到其他疾病的治疗。
Cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) and their activating partners, D-type cyclins, link the extracellular environment with the core cell-cycle machinery. Constitutive activation of cyclin D-CDK4/6 represents the driving force of tumorigenesis in several cancer types. Small-molecule inhibitors of CDK4/6 have been used with great success in the treatment of hormone receptor-positive breast cancers, and are in clinical trials for many other tumor types. Unexpectedly, recent work indicates that inhibition of CDK4/6 affects a wide range of cellular functions, such as tumor cell metabolism or anti-tumor immunity. In this Review, we discuss how recent advances in understanding CDK4/6 biology open new avenues for future use of cyclin D-CDK4/6 inhibitors in cancer treatment. In this Review, Fassl et al. discuss basic biology of CDK4 and CDK6 kinases, studies that led to identification of CDK4/6 as excellent anti-cancer targets, the growing application of CDK4/6 inhibitors in cancer treatment and the promise these compounds hold for future therapies. Cyclins and cyclin-dependent kinases (CDKs) drive cell division. Of particular importance to the cancer field are D-cyclins, which bind and activate CDK4 and CDK6. In normal cells, the activity of cyclin D-CDK4/6 is controlled by the extracellular pro-proliferative or inhibitory signals. In contrast, in many cancers, cyclin D-CDK4/6 kinases are hyperactivated and become independent of the mitogenic stimulation, thereby driving uncontrolled tumor cell proliferation. Mouse genetic experiments established that cyclin D-CDK4/6 kinases are essential for growth of many tumor types, and they represent potential therapeutic targets. Genetic and cell culture studies documented the dependence of breast cancer cells on CDK4/6. Chemical CDK4/6-inhibitors were synthesized and tested in pre-clinical studies. Introduction of these compounds to the clinics represented a breakthrough in breast cancer treatment, and will likely have a major impact on the treatment of many other tumor types. Small-molecule CDK4/6-inhibitors (palbociclib, ribociclib and abemaciclib) have shown impressive results in clinical trials for patients with hormone receptor-positive breast cancers. Addition of CDK4/6-inhibitors to standard endocrine therapy substantially extended the median progression-free survival, and prolonged median overall survival. Consequently, all three CDK4/6-inhibitors received ‘Breakthrough Therapy’ designation status from U.S. Food and Drug Administration, and have been approved for the treatment of women with advanced/metastatic hormone receptor-positive breast cancers. In the last few years, the renewed interest in basic CDK4/6 biology has yielded several surprising discoveries. The emerging concept is that CDK4/6 kinases regulate a much wider set of cellular functions than previously anticipated. Consequently, CDK4/6-inhibitors, beyond inhibiting tumor cell proliferation, affect tumor cells and the tumor environment through mechanisms that are only beginning to be elucidated. For example, inhibition of CDK4/6 affects anti-tumor immunity acting both on tumor cells as well as on the host immune system. Importantly, CDK4/6-inhibitors were shown to greatly enhance the efficacy of immune checkpoint blockade in pre-clinical mouse cancer models. These new concepts are now being tested in clinical trials. Palbociclib, ribociclib and abemaciclib are now being tested in over 300 active or recruiting clinical trials for over 50 tumor types, such as other sub-types of breast cancers (HER2-positive, triple-negative), as well as colon, lung, liver, uterine and ovarian cancers, glioblastoma and various lymphoid malignancies. These trials test CDK4/6-inhibitors in combination with a wide range of therapeutic compounds that target other cancer-relevant pathways. Several other combination treatments were shown to be efficacious in pre-clinical studies and will enter clinical trials in the near future. Another CDK4/6-inhibitor, trilaciclib, is being tested for its ability to shield normal, non-transformed cells of the host from cytotoxic effects of chemotherapy. New CDK4/6-inhibitors have been developed and are being tested in pre-clinical and clinical trials. The major impediment in the therapeutic use of CDK4/6-inhibitors is that patients who initially respond to treatment often develop resistance and eventually succumb to the disease. Moreover, a substantial fraction of tumors shows pre-existing, intrinsic resistance to CDK4/6-inhibitors. One of the main challenges will be to elucidate the full-range of resistance molecular mechanisms. Even with the current, limited knowledge, one can envisage the principles of new, improved approaches which would overcome known resistance mechanisms. Another largely unexplored area is the possible involvement of CDK4/6 in other pathologic states, beyond cancer. This area will be the subject of intense studies and it may extend the utility of CDK4/6-inhibitors to the treatment of other diseases.
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影响因子：
8
作者：
Cao, Joan;Zhu, Zhou;Wei, Ping
通讯作者：
Wei, Ping
影响因子：
11.1
作者：
Dall'Acqua A;Sonego M;Pellizzari I;Pellarin I;Canzonieri V;D'Andrea S;Benevol S;Sorio R;Giorda G;Califano D;Bagnoli M;Militello L;Mezzanzanica D;Chiappetta G;Armenia J;Belletti B;Schiappacassi M;Baldassarre G
通讯作者：
Baldassarre G
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：
4.3
作者：
Dean, Jeffry L.;McClendon, A. Kathleen;Knudsen, Erik S.
通讯作者：
Knudsen, Erik S.
DOI：
10.1158/1078-0432.ccr-18-0410
发表时间：
2018-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
de Leeuw R;McNair C;Schiewer MJ;Neupane NP;Brand LJ;Augello MA;Li Z;Cheng LC;Yoshida A;Courtney SM;Hazard ES;Hardiman G;Hussain MH;Diehl JA;Drake JM;Kelly WK;Knudsen KE
通讯作者：
Knudsen KE