靶向CDK4和CDK6在癌症中的作用

Abstract | 摘要

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 (Cyclin-dependent kinase 4, CDK4)和CDK6是细胞过渡到S期的关键介质，对许多类型的癌症的起始、生长和生存都很重要。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护理的新标准。正如预期的那样，CDK4/6抑制剂在细胞周期的G1期阻滞敏感肿瘤细胞。然而，CDK4/6抑制的影响要广泛得多。对其作用机制的新认识引发了新的治疗机会的识别，包括开发新的联合方案，扩大应用到更广泛的癌症，并作为支持治疗，以改善其他疗法的毒性作用。在临床探索这些新的机会是一项紧迫的优先事项，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塑造这些药物未来的临床发展。我们还讨论了CDK4/6抑制剂耐药性的生物学基础，这是临床肿瘤学中越来越常见的挑战。