The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.
The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies.
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DOI：
10.1016/j.trecan.2016.11.006
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发表时间：
2017-01
期刊：
影响因子：
18.4
通讯作者：
Witkiewicz AK
中科院分区：
文献类型：
--
作者：
Knudsen ES;Witkiewicz AK
CDK 4/6抑制剂已成为一类在许多恶性肿瘤中具有临床活性的强效药物。靶向细胞周期代表了对癌症定义特征的核心攻击。然而，选择性CDK 4/6靶向药物的作用机制在目前的抗癌药物中几乎没有相似之处。值得注意的是，CDK 4/6抑制剂作用于大多数促有丝分裂信号级联的下游，这与临床疗效和耐药性相关。细胞周期过程的核心知识提供了对CDK 4/6抑制剂内在耐药机制的见解;然而，获得性耐药与持久反应的基础才刚刚开始出现。本文综述了CDK 4/6抑制剂的作用机制和生物标志物，以指导CDK 4/6抑制剂的精确使用和合理开发的联合治疗。
CDK4/6 inhibitors have emerged as a powerful class of agents with clinical activity in a number of malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms through which selective CDK4/6 targeted agents act has few parallels in the current pharmaceutical armamentarium against cancer. Notably, CDK4/6 inhibitors act downstream of most mitogenic signaling cascades, which have implications both related to clinical efficacy and resistance. Core knowledge of cell cycle processes has provided insights into mechanisms of intrinsic resistance to CDK4/6 inhibitors; however, the basis of acquired resistance versus durable response is only beginning to emerge. This review focuses on the mechanism of action and biomarkers to direct the precision use of CDK4/6 inhibitors and rationally-developed combination therapies.