Targeting androgen receptor phase separation to overcome antiandrogen resistance

• Published in: Nature chemical biology Vol. 18; no. 12; pp. 1341 - 1350
• Main Authors: Xie, Jingjing, He, Hao, Kong, Wenna, Li, Ziwen, Gao, Zhenting, Xie, Daoqing, Sun, Lin, Fan, Xiaofei, Jiang, Xiangqing, Zheng, Qiangang, Li, Guo, Zhu, Jidong, Zhu, Guangya
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2022; Nature Publishing Group
• Subjects: 631/1647/328; 631/337/572; 631/67/1059; 631/92/613; Alternative splicing; Androgen Antagonists - pharmacology; Androgen Antagonists - therapeutic use; Androgen receptors; Androgens; Antiandrogens; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Castration; Cell Biology; Cell Line, Tumor; Cell proliferation; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Condensates; Drug resistance; Drug Resistance, Neoplasm; Humans; Ligands; Liquid phases; Male; Mutation; Phase separation; Prostate cancer; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - pathology; Receptors; Receptors, Androgen - genetics; Resistant mutant; Transcription
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/s41589-022-01151-y

Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice variants enabling restored AR signaling. Here we show that ligand-activated AR can form transcriptionally active condensates. Both structured and unstructured regions of AR contribute to the effective phase separation of AR and disordered N-terminal domain plays a predominant role. AR liquid–liquid phase separation behaviors faithfully report transcriptional activity and antiandrogen efficacy. Antiandrogens can promote phase separation and transcriptional activity of AR-resistant mutants in a ligand-independent manner. We conducted a phase-separation-based phenotypic screen and identified ET516 that specifically disrupts AR condensates, effectively suppresses AR transcriptional activity and inhibits the proliferation and tumor growth of prostate cancer cells expressing AR-resistant mutants. Our results demonstrate liquid–liquid phase separation as an emerging mechanism underlying drug resistance and show that targeting phase separation may provide a feasible approach for drug discovery. Phase separation of androgen receptor underlies mutation-mediated antiandrogen resistance. A phenotypic screen enabled the discovery of ET516, which disrupts androgen receptor phase separation and effectively suppresses the growth of prostate cancer.