Department of Drug Discovery and Biomedical Sciences, University of South Carolina, 715, Sumter Street, CLS609D, Columbia, SC, 29208, USA.
J Mol Med (Berl). 2021 Dec;99(12):1691-1710. doi: 10.1007/s00109-021-02136-5. Epub 2021 Oct 8.
Estrogen receptor-positive (ER +) breast cancer accounts for approximately 75% of all breast cancers. Endocrine therapies, including selective ER modulators (SERMs), aromatase inhibitors (AIs), and selective ER down-regulators (SERDs) provide substantial clinical benefit by reducing the risk of disease recurrence and mortality. However, resistance to endocrine therapies represents a major challenge, limiting the success of ER + breast cancer treatment. Mechanisms of endocrine resistance involve alterations in ER signaling via modulation of ER (e.g., ER downregulation, ESR1 mutations or fusions); alterations in ER coactivators/corepressors, transcription factors (TFs), nuclear receptors and epigenetic modulators; regulation of signaling pathways; modulation of cell cycle regulators; stress signaling; and alterations in tumor microenvironment, nutrient stress, and metabolic regulation. Current therapeutic strategies to improve outcome of endocrine-resistant patients in clinics include inhibitors against mechanistic target of rapamycin (mTOR), cyclin-dependent kinase (CDK) 4/6, and the phosphoinositide 3-kinase (PI3K) subunit, p110α. Preclinical studies reveal novel therapeutic targets, some of which are currently tested in clinical trials as single agents or in combination with endocrine therapies, such as ER partial agonists, ER proteolysis targeting chimeras (PROTACs), next-generation SERDs, AKT inhibitors, epidermal growth factor receptor 1 and 2 (EGFR/HER2) dual inhibitors, HER2 targeting antibody-drug conjugates (ADCs) and histone deacetylase (HDAC) inhibitors. In this review, we summarize the established and emerging mechanisms of endocrine resistance, alterations during metastatic recurrence, and discuss the approved therapies and ongoing clinical trials testing the combination of novel targeted therapies with endocrine therapy in endocrine-resistant ER + breast cancer patients.
雌激素受体阳性（ER+）乳腺癌约占所有乳腺癌的 75%。内分泌治疗，包括选择性雌激素受体调节剂（SERMs）、芳香酶抑制剂（AIs）和选择性雌激素受体降解剂（SERDs），通过降低疾病复发和死亡的风险，为患者带来了显著的临床获益。然而，内分泌治疗的耐药性是一个主要挑战，限制了 ER+乳腺癌治疗的成功。内分泌耐药的机制涉及通过调节 ER（如 ER 下调、ESR1 突变或融合）改变 ER 信号；改变 ER 共激活剂/共抑制物、转录因子（TFs）、核受体和表观遗传调节剂；调节信号通路；调节细胞周期调节剂；应激信号；以及改变肿瘤微环境、营养应激和代谢调节。目前，为改善临床中内分泌耐药患者的预后而采用的治疗策略包括针对雷帕霉素（mTOR）、细胞周期蛋白依赖性激酶（CDK）4/6 和磷酸肌醇 3-激酶（PI3K）亚单位 p110α 的抑制剂。临床前研究揭示了一些新的治疗靶点，其中一些目前正在临床试验中作为单一药物或与内分泌治疗联合进行测试，如 ER 部分激动剂、雌激素受体降解靶向嵌合体（PROTACs）、下一代 SERDs、AKT 抑制剂、表皮生长因子受体 1 和 2（EGFR/HER2）双重抑制剂、HER2 靶向抗体药物偶联物（ADC）和组蛋白去乙酰化酶（HDAC）抑制剂。在这篇综述中，我们总结了内分泌耐药的既定和新兴机制、转移复发过程中的改变，并讨论了已批准的治疗方法和正在进行的临床试验，这些试验测试了新型靶向治疗与内分泌治疗联合用于内分泌耐药的 ER+乳腺癌患者。
