The introduction of cyclin-dependent kinase 4/6 inhibitors (CKIs) has marked a major development in the standard treatment of advanced breast cancer. Extensive preclinical, translational and clinical research efforts into CKI agents are ongoing, and clinical application of this class of systemic anti-cancer therapy is anticipated to expand beyond metastatic breast cancer treatment. Emerging evidence indicates that mechanisms by which CKI agents exert their therapeutic effect transcend their initially expected impacts on cell cycle control into the realms of cancer immunology and metabolism. The recent expansion in our understanding of the multifaceted impact of CKIs on tumour biology has the potential to improve clinical study design, therapeutic strategies and ultimately patient outcomes. This review contextualises the current status of CKI therapy by providing an overview of the original and emerging insights into mechanisms of action and the evidence behind their current routine use in breast cancer management. Recent preclinical and clinical studies into CKIs across tumour types are discussed, including a synthesis of the more than 300 clinical trials of CKI-combination treatments registered as of November 2020. Key challenges and opportunities anticipated in the 2020s are explored, including treatment resistance, combination therapy strategies and potential biomarker development.

中文翻译：

---

细胞周期蛋白依赖性激酶抑制剂的抗癌治疗：影响和挑战

细胞周期蛋白依赖性激酶 4/6 抑制剂 (CKI) 的引入标志着晚期乳腺癌标准治疗的重大发展。对 CKI 药物的广泛临床前、转化和临床研究工作正在进行中，预计此类全身性抗癌治疗的临床应用将扩展到转移性乳腺癌治疗之外。新出现的证据表明，CKI 药物发挥治疗作用的机制超越了最初预期的对细胞周期控制的影响，进入癌症免疫学和代谢领域。最近我们对 CKI 对肿瘤生物学的多方面影响的理解有所扩展，这有可能改善临床研究设计、治疗策略并最终改善患者预后。本综述通过概述对作用机制的原始和新兴见解以及它们目前在乳腺癌管理中常规使用的证据，将 CKI 治疗的当前状态置于背景中。讨论了最近对跨肿瘤类型 CKI 的临床前和临床研究，包括截至 2020 年 11 月注册的 300 多项 CKI 联合治疗临床试验的综合。探讨了 2020 年代预期的主要挑战和机遇，包括治疗耐药性、联合治疗治疗策略和潜在的生物标志物开发。