Cell cycle dysregulation is a hallmark of cancer that promotes eccessive cell division. Cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) are key molecules in the G1-to-S phase cell cycle transition and are crucial for the onset, survival, and progression of breast cancer (BC). Small-molecule CDK4/CDK6 inhibitors (CDK4/6i) block phosphorylation of tumor suppressor Rb and thus restrain susceptible BC cells in G1 phase. Three CDK4/6i are approved for the first-line treatment of patients with advanced/metastatic hormone receptor-positive (HR)/human epidermal growth factor receptor 2-negative (HER2) BC in combination with endocrine therapy (ET). Though this has improved the clinical outcomes for survival of BC patients, there is no established standard next-line treatment to tackle drug resistance. Recent studies suggest that CDK4/6i can modulate other distinct effects in both BC and breast stromal compartments, which may provide new insights into aspects of their clinical activity. This review describes the biochemistry of the CDK4/6-Rb-E2F pathway in HR BC, then discusses how CDK4/6i can trigger other effects in BC/breast stromal compartments, and finally outlines the mechanisms of CDK4/6i resistance that have emerged in recent preclinical studies and clinical cohorts, emphasizing the impact of these findings on novel therapeutic opportunities in BC.

中文翻译：

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激素受体阳性乳腺癌治疗中 CDK4/CDK6 抑制剂的敏感性和耐药机制


细胞周期失调是癌症的一个标志，它会促进细胞过度分裂。细胞周期蛋白依赖性激酶 4 (CDK4) 和细胞周期蛋白依赖性激酶 6 (CDK6) 是 G1 至 S 期细胞周期转变的关键分子，对于乳腺癌 (BC) 的发病、生存和进展至关重要。小分子 CDK4/CDK6 抑制剂 (CDK4/6i) 阻断抑癌基因 Rb 的磷酸化，从而将易感 BC 细胞抑制在 G1 期。三种 CDK4/6i 被批准用于与内分泌治疗 (ET) 联合治疗晚期/转移性激素受体阳性 (HR)/人表皮生长因子受体 2 阴性 (HER2) BC 患者的一线治疗。尽管这改善了 BC 患者生存的临床结果，但尚无既定的标准下线治疗方法来解决耐药性。最近的研究表明，CDK4/6i 可以调节 BC 和乳腺基质室中的其他独特作用，这可能为其临床活性的各个方面提供新的见解。这篇综述描述了 HR BC 中 CDK4/6-Rb-E2F 通路的生物化学，然后讨论了 CDK4/6i 如何在 BC/乳腺基质区室中触发其他效应，最后概述了在 HR BC 中出现的 CDK4/6i 耐药机制。最近的临床前研究和临床队列，强调这些发现对 BC 的新治疗机会的影响。