1. Academic Validation
  2. Chemical degrader enhances the treatment of androgen receptor-positive triple-negative breast cancer

Chemical degrader enhances the treatment of androgen receptor-positive triple-negative breast cancer

  • Arch Biochem Biophys. 2022 May 30;721:109194. doi: 10.1016/j.abb.2022.109194.
Yingchun Wu 1 Jinqiu Xue 2 Jia Li 3
Affiliations

Affiliations

  • 1 Ultrasonic Department, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 2 Department of Breast Surgery, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 3 Department of Ultrasound, Zhongda Hospital, Southeast University, Nanjing, China. Electronic address: 13951609892@163.com.
Abstract

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.

Keywords

Androgen receptor; Proteolysis-targeting chimera; Therapeutic treatment; Triple-negative breast cancer.

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