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. Epub 2022 Oct 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / pharmacology
  • Androgen Antagonists / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Ligands
  • Male
  • Prostatic Neoplasms* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Receptors, Androgen / genetics


  • Receptors, Androgen
  • Androgen Antagonists
  • Ligands

Associated data

  • figshare/10.6084/m9.figshare.20484396