内分泌疗法（ET）结合细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）目前是治疗大多数激素受体阳性、人表皮生长因子受体（HER2）阴性晚期乳腺癌的标准一线治疗。然而，耐药性对ET和CDK4/6i治疗是不可避免的问题。优化的疾病进展后治疗方案及其顺序在快速变化的治疗格局中仍在不断发展。在本综述中，我们总结了对ET和CDK4/6i产生耐药性的机制，这些机制可以广义上归类为影响细胞周期介体以及激活替代信号通路的变化。最近的临床试验已针对这些靶点和通路进行了研究，包括雌激素和雄激素受体、PI3K/AKT/mTOR和MAPK通路、FGFR和HER2等酪氨酸激酶受体、同源重组修复通路、细胞周期和细胞死亡的其他组分。我们描述了这些临床试验使用小分子抑制剂、抗体药物联合治疗和免疫疗法的结果，为如何规避耐药性提供了见解，并讨论了其中一些策略在临床中未能展现出益处的原因。肿瘤异质性、信号通路的适应性重构和剂量限制性毒性所带来的挑战强调了在精准医疗时代中，阐明每个患者的最新肿瘤生物学，以及开发具有改善的治疗指数的治疗方法的必要性。© 2023. Springer Nature Limited.

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.© 2023. Springer Nature Limited.