Wu Yingchun, Xue Jinqiu, Li Jia
Ultrasonic Department, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Breast Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Arch Biochem Biophys. 2022 May 30;721:109194. doi: 10.1016/j.abb.2022.109194. Epub 2022 Mar 23.
Androgen receptor (AR) is a promising therapeutic target for AR-positive triple-negative breast cancer (TNBC). However, clinical trials of AR inhibitors only reveal modest therapeutic efficacy for AR-positive TNBC, and drug resistance is also inevitable. To address these challenges, we herein report the use of an AR-targeting proteolysis targeting chimera (AR-PROTAC) to treat AR-positive TNBC. We demonstrated that AR-PROTAC potently degraded AR protein via the ubiquitin-proteasome pathway in AR-positive TNBC BT549 cells, with a half degradation concentration of ∼46.9 nM. By evaluating the therapeutic efficacies in vitro and in vivo, we validated that AR-PROTAC was superior to enzalutamide, an AR inhibitor. Specifically, AR-PROTAC at 100 nM reduced BT549 cell viability by up to ∼80%, and AR-PRTOAC at 10 mg/kg suppressed tumor growth by ∼60% when administrated intratumorally in subcutaneous BT549 tumor mice model. Overall, these results demonstrate for the first time that PROTAC holds promise to enhance the treatment of AR-positive TNBC.
雄激素受体（AR）是雄激素受体阳性三阴性乳腺癌（TNBC）一个很有前景的治疗靶点。然而，AR抑制剂的临床试验仅显示出对AR阳性TNBC有适度的治疗效果，而且耐药性也不可避免。为应对这些挑战，我们在此报告使用一种靶向AR的蛋白酶体靶向嵌合体（AR-PROTAC）来治疗AR阳性TNBC。我们证明，AR-PROTAC通过泛素-蛋白酶体途径在AR阳性TNBC的BT549细胞中有效降解AR蛋白，半降解浓度约为46.9 nM。通过评估体外和体内的治疗效果，我们验证了AR-PROTAC优于AR抑制剂恩杂鲁胺。具体而言，100 nM的AR-PROTAC可使BT549细胞活力降低高达约80%，在皮下BT549肿瘤小鼠模型中瘤内注射10 mg/kg的AR-PRTOAC时，可使肿瘤生长抑制约60%。总体而言，这些结果首次证明PROTAC有望增强对AR阳性TNBC的治疗。
