NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide

Drug Resist Updat. 2023 Sep:70:100990. doi: 10.1016/j.drup.2023.100990. Epub 2023 Jul 17.

Abstract

This study investigated cellular mechanisms in steroidogenesis responsible for treatment resistance to the novel antiandrogen agent darolutamide in prostate cancer. HSD3B1 was overexpressed in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, HSD3B1 knockdown increased cellular sensitivity to darolutamide. Similarly, its upstream regulator NR5A2 was up-regulated in darolutamide-resistant cells and induced by darolutamide treatment and AR knockdown. Inversely, NR5A2 knockdown and NR5A2 inhibitor ML180 decreased expression of various steroidogenic enzymes including HSD3B1, leading to increased cellular sensitivity to darolutamide. The NR5A2/HSD3B1 pathway promoted cellular resistance to darolutamide and targeting NR5A2/HSD3B1 pathway is a promising therapeutic strategy to overcome darolutamide resistance.

Keywords: Androgen-deprivation therapy; Darolutamide; HSD3B1; NR5A2; Prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists* / pharmacology
  • Androgen Antagonists* / therapeutic use
  • Androgen Receptor Antagonists / pharmacology
  • Androgen Receptor Antagonists / therapeutic use
  • Humans
  • Male
  • Multienzyme Complexes / metabolism
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / metabolism
  • Receptors, Cytoplasmic and Nuclear / metabolism

Substances

  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • darolutamide
  • Multienzyme Complexes
  • NR5A2 protein, human
  • Receptors, Cytoplasmic and Nuclear