协和医学杂志

2020, (06) 758-765

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细胞周期依赖性激酶4/6抑制剂在恶性肿瘤治疗中的应用及耐药机制
Application of Cyclin-dependent Kinase 4/6 Inhibitors in the Treatment of Malignancies and the Mechanism of Drug Resistance

唐辉;应红艳;白春梅;
TANG Hui;YING Hong-yan;BAI Chun-mei;Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College;

摘要(Abstract):

增殖失控是恶性肿瘤的重要特征之一。细胞周期依赖性激酶4/6(cyclin-dependent kinase 4/6, CDK4/6)抑制剂能作用于各种原因导致的过度活化的CDK4/6,恢复正常细胞周期,并可通过增强免疫、改变肿瘤微环境等发挥抗肿瘤作用。目前,CDK4/6抑制剂在激素受体阳性乳腺癌治疗中取得了良好疗效,已被批准联合内分泌治疗作为此类肿瘤的一线治疗方案,在其他肿瘤中的应用亦逐渐开展,疗效有待验证。对CDK4/6抑制剂天然或获得性耐药是影响其疗效的重要因素,目前激素受体阳性(主要为雌激素受体阳性)能较为准确预测内分泌联合CDK4/6抑制剂治疗的反应性,其他标志物需进一步探索和验证。本文对CDK4/6抑制剂治疗恶性肿瘤的作用机制、应用现状及耐药机制进行梳理和总结,并对当前CDK4/6抑制剂治疗乳腺癌尚存争议的临床决策问题作简要讨论。
Uncontrolled cell proliferation is one of the important hallmarks of malignancies. Cyclin-dependent kinase 4/6(CDK4/6) inhibitors act on CDK4/6 that is over activated by various causes. CDK4/6 inhibitors play anti-tumor roles by restoring normal cell cycle, enhancing anti-tumor immunity, and reforming tumor microenvironment. Currently, CDK4/6 inhibitors have been confirmed to be effective in hormone-receptor-positive breast cancer and were approved as the first-line treatment for this breast cancer in combination with endocrine therapy. Furthermore, CDK4/6 inhibitors have been gradually applied to the treatment of other tumors, but the efficacy remains to be evaluated. Natural or acquired resistance to CDK4/6 inhibitors is a major factor affecting their efficacy. However, at present, only hormone receptor-positive(mainly estrogen receptor-positive) can relatively accurately predict the responsiveness of CDK4/6 inhibitors in combination with endo-crine treatment, and other markers need to be further explored and verified in clinical studies. The mechanism of action, the status of application, and mechanisms of drug-resistance of CDK4/6 inhibitors in the treatment of malignancies were reviewed and summarized in this paper, and the controversy over clinical decision-making on the treatment of breast cancer with CDK4/6 inhibitors was briefly discussed.

关键词(KeyWords): 细胞周期依赖性激酶4/6抑制剂;细胞周期调控;乳腺癌;治疗;耐药机制
cyclin-dependent kinase 4/6 inhibitors;cell cycle control;breast cancer;treatment;mechanism of drug resistance

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基金项目(Foundation): 中国医学科学院医学与健康科技创新工程(2016-12M-1-001)~~

作者(Author): 唐辉;应红艳;白春梅;
TANG Hui;YING Hong-yan;BAI Chun-mei;Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College;

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