Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.

细胞周期蛋白依赖性激酶 4 (CDK4) 和 CDK6 是细胞转变为 S 期的关键介质，对许多癌症类型的发生、生长和存活都很重要。CDK4/6 的药理学抑制剂已迅速成为晚期激素受体阳性乳腺癌患者的新标准治疗。正如预期的那样，CDK4/6 抑制剂将敏感的肿瘤细胞阻滞在细胞周期的 G1 期。然而，CDK4/6 抑制的影响更为广泛。对其作用机制的新见解引发了对新治疗机会的识别，包括开发新的联合治疗方案、将应用扩大到更广泛的癌症范围以及用作支持性治疗以改善其他疗法的毒性作用。在临床中探索这些新机会是当务之急，但在许多情况下尚未得到充分解决。在这里，我们提供了一个框架来概念化 CDK4/6 抑制剂在癌症中的活性，并解释了这个框架如何影响这些药物未来的临床开发。我们还讨论了 CDK4/6 抑制剂耐药性的生物学基础，这是临床肿瘤学中日益普遍的挑战。