Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Deparment of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Mol Cancer Ther. 2021 Jun;20(6):1062-1071. doi: 10.1158/1535-7163.MCT-20-0807. Epub 2021 Mar 15.
Triple-negative breast cancer (TNBC) is an aggressive subtype, with a peak recurrence rate within the first few years after diagnosis. Few targeted therapies are available to treat this breast cancer subtype, defined by the lack of estrogen receptor (ER) and progesterone receptor and without amplification of human epidermal growth factor receptor 2 (HER2). Although cell cycle cyclin-dependent kinase (CDK) 4/6 inhibitors are approved for treatment of ER-positive (ER) breast cancer, they have not proven effective as monotherapy in patients with TNBC. The androgen receptor (AR) has emerged as a therapeutic target in a subset of TNBCs and with significant clinical benefit observed in multiple trials. The purpose of this study was to investigate the preclinical activity of the CDK4/6 inhibitor, abemaciclib, in combination with an agent that targets both androgen biosynthesis and AR activity, seviteronel, using TNBC cell lines expressing high AR, cell line xenografts, and an AR-positive (AR), androgen-responsive TNBC patient-derived xenograft (PDX). Single-cell RNA sequencing demonstrated heterogeneity in levels, even in a highly AR cell line, and identified cell cycle pathway activation in AR- versus AR-expressing cells. Combination treatment with the cell cycle CDK4/6 inhibitor, abemaciclib, and seviteronel showed synergy in an AR TNBC model compared with each drug alone. Although cell cycle inhibitors are FDA approved for use in ER breast cancer, our studies suggest that they may also be effective in AR TNBC, perhaps combined with AR-targeted agents.
三阴性乳腺癌（TNBC）是一种侵袭性亚型，在诊断后最初几年内复发率最高。目前仅有少数靶向疗法可用于治疗这种乳腺癌亚型，其特征是缺乏雌激素受体（ER）和孕激素受体，且人表皮生长因子受体 2（HER2）无扩增。尽管细胞周期周期蛋白依赖性激酶（CDK）4/6 抑制剂已获批用于治疗 ER 阳性（ER）乳腺癌，但在 TNBC 患者中作为单药治疗并未证明有效。雄激素受体（AR）已成为 TNBC 亚组的治疗靶点，多项试验观察到显著的临床获益。本研究旨在探讨 CDK4/6 抑制剂 abemaciclib 与同时靶向雄激素生物合成和 AR 活性的药物 seviteronel 联合应用在高表达 AR 的 TNBC 细胞系、细胞系异种移植瘤和 AR 阳性（AR）、雄激素反应性 TNBC 患者来源异种移植瘤（PDX）中的临床前活性。单细胞 RNA 测序表明，即使在高度表达 AR 的细胞系中， 水平也存在异质性，并在 AR 表达细胞和 AR 非表达细胞中鉴定出细胞周期通路的激活。与单独使用每种药物相比，细胞周期 CDK4/6 抑制剂 abemaciclib 与 seviteronel 联合治疗 AR TNBC 模型显示出协同作用。尽管细胞周期抑制剂已获 FDA 批准用于 ER 乳腺癌，但我们的研究表明，它们在 AR TNBC 中也可能有效，或许可以与 AR 靶向药物联合使用。
