随着细胞周期蛋白依赖性激酶 (CDK)4/6 抑制剂的出现，激素受体阳性 (HR ) 乳腺癌的治疗格局发生了重大转变，特别是与内分泌治疗作为主要治疗方案相结合。然而，HR 转移性乳腺癌中针对 CDK4/6 抑制剂的耐药机制的演变给该疾病的治疗带来了巨大的挑战。这篇综述探讨了耐药性背后的多样化基因组景观，包括细胞周期的紊乱、致癌信号通路的偏差、DNA损伤反应（DDR）机制的缺陷以及肿瘤微环境（TME）的变化。此外，它还讨论了克服耐药性的潜在策略，包括内分泌治疗的进展、细胞周期成分的靶向抑制、AKT/mTOR 激活的抑制、FGFR 通路的探索、抗体药物偶联物 (ADC) 的利用以及免疫整合检查点抑制剂 (ICIs) 与内分泌治疗和 CDK4/6 抑制剂相结合，为在治疗挑战中改善患者预后提供途径。版权所有 © 2024。由 Elsevier B.V. 出版。

The therapeutic landscape for hormone receptor-positive (HR+) breast carcinoma has undergone a significant transformation with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors, particularly in combination with endocrine therapy as the primary regimen. However, the evolution of resistance mechanisms in response to CDK4/6 inhibitors in HR+ metastatic breast cancer presents substantial challenges in managing the disease. This review explores the diverse genomic landscape underlying resistance, including disturbances in the cell cycle, deviations in oncogenic signaling pathways, deficiencies in DNA damage response (DDR) mechanisms, and changes in the tumor microenvironment (TME). Additionally, it discusses potential strategies to surmount resistance, including advancements in endocrine therapy, targeted inhibition of cell cycle components, suppression of AKT/mTOR activation, exploration of the FGFR pathway, utilization of antibody-drug conjugates (ADCs), and integration of immune checkpoint inhibitors (ICIs) with endocrine therapy and CDK4/6 inhibitors, providing pathways for enhancing patient outcomes amidst treatment challenges.Copyright © 2024. Published by Elsevier B.V.