Inhibitors of cyclin-dependent kinases (CDKs) 4/6 have emerged as a powerful class of agents with clinical activity in several malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms of action of agents selectively targeting CDK4/6 have few parallels in the current pharmaceutical armamentarium against cancer. Notably, CDK4/6 inhibitors act downstream of most mitogenic signaling cascades, and this has implications for both clinical efficacy and resistance. Core knowledge of cell-cycle processes has provided insights into the 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 of CDK4/6 inhibitors as well as on biomarkers to direct their precision use in rationally developed combination therapies.

细胞周期蛋白依赖性激酶（CDKs）4/6的抑制剂已成为一类功能强大的药物，在多种恶性肿瘤中均具有临床活性。靶向细胞周期代表了对癌症定义特征的核心攻击。但是，选择性靶向CDK4 / 6的药物的作用机制在当前的抗癌药物装备中几乎没有相似之处。值得注意的是，CDK4 / 6抑制剂在大多数促有丝分裂信号级联反应的下游起作用，这对临床疗效和耐药性都有影响。细胞周期过程的核心知识提供了对CDK4 / 6抑制剂内在抗性机制的见解。然而，获得性抵抗力与持久响应性的基础才刚刚出现。