Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment.

Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment. Neoplasia. 2020 Jan 10;22(2):111-119 Authors: Kregel S, Wang C, Han X, Xiao L, Fernandez-Salas E, Bawa P, McCollum BL, Wilder-Romans K, Apel IJ, Cao X, Speers C, Wang S, Chinnaiyan AM Abstract Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation,...
Source: Neoplasia - Category: Cancer & Oncology Authors: Tags: Neoplasia Source Type: research