克服激素受体阳性、人表皮生长因子受体2阴性乳腺癌对细胞周期蛋白依赖性激酶4/6抑制剂的耐药性：创新联合疗法与新兴策略

Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative Combinations and Emerging Strategies.

作者信息

Giugliano Federica, De Angelis Carmine, Pistilli Barbara, Viale Giulia, Bianchini Giampaolo, Giuliano Mario, Malorni Luca, Taurelli Salimbeni Beatrice, Esposito Angela, Giordano Antonio, Yap Timothy A, Curigliano Giuseppe, Criscitiello Carmen

机构信息

INSERM U981, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Gustave Roussy, Villejuif, France; Department of Oncology and Hematology-Oncology, University of Milano, Milan, Italy.

Clinical and Translational Oncology, Scuola Superiore Meridionale Via Mezzocannone, 4 80134 Naples, Italy.

出版信息

Cancer Treat Rev. 2025 Sep;139:102980. doi: 10.1016/j.ctrv.2025.102980. Epub 2025 Jun 14.

DOI:10.1016/j.ctrv.2025.102980

PMID:40544690

Abstract

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) improve outcomes patients affected by metastatic and early-stage hormone receptor-positive, HER2-negative breast cancer. However, approximately 20% of these tumors exhibit intrinsic resistance to such therapies, and most develop acquired resistance mechanisms that drive progression. Biomarker analyses of biological samples from patients treated with CDK4/6i plus ET have identified potential targets for therapeutic combinations. In this review, we discuss the mechanisms of action and resistance to CDK4/6i, providing a comprehensive overview of emerging efficacy and safety data, biomarker-driven strategies, and ongoing clinical trials. Finally, we delineate key research priorities aimed at guiding the development of innovative therapeutic combinations.

摘要

细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）与内分泌治疗（ET）联合使用可改善转移性和早期激素受体阳性、人表皮生长因子受体2阴性乳腺癌患者的预后。然而，这些肿瘤中约20%对此类治疗表现出内在抗性，且大多数会产生导致疾病进展的获得性抗性机制。对接受CDK4/6i加ET治疗的患者的生物样本进行的生物标志物分析已确定了联合治疗的潜在靶点。在本综述中，我们讨论了CDK4/6i的作用机制和抗性，全面概述了新出现的疗效和安全性数据、生物标志物驱动的策略以及正在进行的临床试验。最后，我们阐述了旨在指导创新联合治疗开发的关键研究重点。