Cancer Research Institute, Seoul National University, Seoul, Korea.
Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Mol Cancer Ther. 2018 Dec;17(12):2507-2518. doi: 10.1158/1535-7163.MCT-18-0234. Epub 2018 Sep 19.
The androgen receptor (AR) is expressed in 60%-70% of breast cancers regardless of estrogen receptor status, and has been proposed as a therapeutic target in breast cancers that retain AR. In this study, the authors aimed to investigate a new treatment strategy using a novel AR inhibitor AZD3514 in breast cancer. AZD3514 alone had a minimal antiproliferative effect on most breast cancer cell lines irrespective of AR expression level, but it downregulated the expressions of DNA damage response (DDR) molecules, including ATM and chk2, which resulted in the accumulation of damaged DNA in some breast cancer cells. Furthermore, AZD3514 enhanced cellular sensitivity to a PARP inhibitor olaparib by blocking the DDR pathway in breast cancer cells. Furthermore, the downregulation of NKX3.1 expression in MDA-MB-468 cells by AZD3514 occurred in parallel with the suppression of ATM-chk2 axis activation, and the suppression of NKX3.1 by AZD3514 was found to result from AZD3514-induced TOPORS upregulation and a resultant increase in NKX3.1 degradation. The study shows posttranslational regulation of NKX3.1 via TOPORS upregulation by AZD3514-induced ATM inactivation-increased olaparib sensitivity in AR-positive and TOPORS-expressing breast cancer cells, and suggests the antitumor effect of AZD3514/olaparib cotreatment is caused by compromised DDR activity in breast cancer cell lines and in a xenograft model. These results provide a rationale for future clinical trials of olaparib/AR inhibitor combination treatment in breast cancer.
雄激素受体 (AR) 在 60%-70%的乳腺癌中表达，无论雌激素受体状态如何，并且已被提议作为保留 AR 的乳腺癌的治疗靶点。在这项研究中，作者旨在研究使用新型 AR 抑制剂 AZD3514 在乳腺癌中的新治疗策略。AZD3514 单独使用对大多数乳腺癌细胞系的增殖作用很小，无论 AR 表达水平如何，但它下调了 DNA 损伤反应 (DDR) 分子的表达，包括 ATM 和 chk2，这导致一些乳腺癌细胞中受损 DNA 的积累。此外，AZD3514 通过阻断 DDR 通路增强了乳腺癌细胞对 PARP 抑制剂奥拉帕利的细胞敏感性。此外，AZD3514 下调 MDA-MB-468 细胞中 NKX3.1 的表达与抑制 ATM-chk2 轴的激活平行发生，并且发现 AZD3514 下调 NKX3.1 是由于 AZD3514 诱导 TOPORS 上调和 NKX3.1 降解增加所致。该研究表明，通过 AZD3514 诱导的 ATM 失活导致 TOPORS 上调，从而对 AR 阳性和 TOPORS 表达的乳腺癌细胞中的 NKX3.1 进行翻译后调节，增加了奥拉帕利的敏感性，提示 AZD3514/奥拉帕利联合治疗的抗肿瘤作用是由于乳腺癌细胞系和异种移植模型中 DDR 活性受损所致。这些结果为奥拉帕利/AR 抑制剂联合治疗在乳腺癌中的未来临床试验提供了依据。
