Targeting androgen receptor phase separation to overcome antiandrogen resistance

  • Nat Chem Biol. 2022 Dec;18(12):1341-1350. doi: 10.1038/s41589-022-01151-y.
Jingjing Xie  #  1  2 ,  Hao He  #  2 ,  Wenna Kong  1  2 ,  Ziwen Li  1 ,  Zhenting Gao  2 ,  Daoqing Xie  2 ,  Lin Sun  1  2 ,  Xiaofei Fan  2 ,  Xiangqing Jiang  2 ,  Qiangang Zheng  2 ,  Guo Li  2 ,  Jidong Zhu  3 ,  Guangya Zhu  4  5
Affiliations
  • 1. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 2. Etern Biopharma, Shanghai, China.
  • 3. Etern Biopharma, Shanghai, China. [email protected].
  • 4. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 5. Lingang Laboratory, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 36229685 DOI: 10.1038/s41589-022-01151-y
Abstract

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.

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