da Silva Jessé Lopes, Oliveira Leandro Jonata de Carvalho, de Resende Cristiano Augusto Andrade, Reinert Tomas, de Albuquerque Lucas Zanetti, Leite da Silva Luís Felipe, Mano Max Senna
Division of Clinical Research and Technological Development, Brazilian National Cancer Institute, 37 Andre Cavalcanti Street, 5th Floor, Annex Building, Rio de Janeiro 20231050, Brazil.
Oncoclínicas&Co, São Paulo, Brazil.
Ther Adv Med Oncol. 2025 Jul 10;17:17588359251353623. doi: 10.1177/17588359251353623. eCollection 2025.
This narrative review explores the mechanisms underlying resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor (HR)-positive metastatic breast cancer (MBC), a critical challenge in contemporary oncology. Despite the proven efficacy of CDK4/6i in improving clinical outcomes, both intrinsic and acquired resistance remain substantial challenges. We discuss clinical data that underscore pivotal molecular alterations associated with resistance, including mutations in the (), germline variants, aberrations in the gene that activate the phosphatidylinositol 3-kinase/protein kinase B (AKT)/mammalian target of rapamycin signaling cascade, and modifications in fibroblast growth factor receptor signaling. Additional resistance mechanisms-such as the loss of the tumor suppressor gene and the dysregulation of cell cycle regulators like and -are also explored. The role of circulating tumor DNA analysis in tracking genomic changes during therapy is also considered. Furthermore, the review assesses emerging therapeutic strategies, particularly combination therapies that target alternative pathways to counteract resistance mechanisms. By synthesizing current evidence and providing actionable insights, this review aims to enhance our understanding of endocrine resistance mechanisms among clinical oncologists and gives them some future perspectives to expand strategies to overcome this challenge.
本叙述性综述探讨了激素受体（HR）阳性转移性乳腺癌（MBC）对细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）耐药的潜在机制，这是当代肿瘤学中的一项关键挑战。尽管CDK4/6i在改善临床结局方面已证实具有疗效，但固有耐药和获得性耐药仍然是重大挑战。我们讨论了强调与耐药相关的关键分子改变的临床数据，包括（）中的突变、种系变异、激活磷脂酰肌醇3激酶/蛋白激酶B（AKT）/雷帕霉素哺乳动物靶标信号级联反应的基因畸变，以及成纤维细胞生长因子受体信号传导的改变。还探讨了其他耐药机制，如肿瘤抑制基因的缺失以及细胞周期调节因子如和的失调。还考虑了循环肿瘤DNA分析在追踪治疗期间基因组变化中的作用。此外，该综述评估了新兴的治疗策略，特别是针对替代途径以对抗耐药机制的联合疗法。通过综合当前证据并提供可行的见解，本综述旨在增进临床肿瘤学家对内分泌耐药机制的理解，并为他们提供一些未来的观点，以扩展克服这一挑战的策略。
