Endocrine therapy (ET) with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is currently the standard first-line treatment for most patients with hormone receptor (HR) positive, human epidermal growth factor receptor (HER2) negative advanced breast cancer. However, resistance to ET and CDK4/6i inevitably ensues. The optimal post-progression treatment regimens and their sequencing continue to evolve in the rapidly changing treatment landscape. In this review, we summarize the mechanisms of resistance to ET and CDK4/6i, which can be broadly classified as alterations affecting cell cycle mediators and activation of alternative signaling pathways. Recent clinical trials have been directed at the targets and pathways implicated, including estrogen and androgen receptors, PI3K/AKT/mTOR and MAPK pathways, tyrosine kinase receptors such as FGFR and HER2, homologous recombination repair pathway, other components of the cell cycle and cell death. We describe the findings from these clinical trials using small molecule inhibitors, antibody–drug conjugates and immunotherapy, providing insights into how these novel strategies may circumvent treatment resistance, and discuss how some have not translated into clinical benefit. The challenges posed by tumor heterogeneity, adaptive rewiring of signaling pathways and dose-limiting toxicities underscore the need to elucidate the latest tumor biology in each patient, and develop treatments with improved therapeutic index in the era of precision medicine.

使用细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）进行内分泌治疗（ET）目前是大多数激素受体（HR）阳性、人表皮生长因子受体（HER2）阴性晚期乳腺癌患者的标准一线治疗。然而，对 ET 和 CDK4/6i 的抵抗不可避免地随之而来。最佳的进展后治疗方案及其排序在快速变化的治疗环境中不断发展。在这篇综述中，我们总结了 ET 和 CDK4/6i 的耐药机制，可大致分为影响细胞周期介质的改变和替代信号通路的激活。最近的临床试验针对相关靶点和通路，包括雌激素和雄激素受体、PI3K/AKT/mTOR 和 MAPK 通路、酪氨酸激酶受体（如 FGFR 和 HER2）、同源重组修复通路、细胞周期和细胞的其他组成部分。死亡。我们描述了这些使用小分子抑制剂、抗体药物偶联物和免疫疗法的临床试验的结果，提供了有关这些新策略如何规避治疗耐药性的见解，并讨论了其中一些策略为何未能转化为临床益处。肿瘤异质性、信号通路的适应性重连和剂量限制毒性带来的挑战强调需要阐明每个患者的最新肿瘤生物学，并在精准医学时代开发具有改善治疗指数的治疗方法。