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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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NR5A2/HSD3B1 pathway promotes cellular resistance to second-generation antiandrogen darolutamide

Masaki Shiota1, Miho Ushijima1, Shigehiro Tsukahara1

  • 1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|July 21, 2023
PubMed

Insights

Overcoming prostate cancer treatment resistance to darolutamide involves targeting the NR5A2/HSD3B1 pathway. This pathway promotes resistance, and inhibiting it enhances cellular sensitivity to darolutamide.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Prostate cancer treatment resistance to antiandrogen agents like darolutamide is a significant clinical challenge.
  • Understanding the cellular mechanisms driving this resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the role of steroidogenesis in darolutamide resistance in prostate cancer.
  • To identify key molecular pathways and regulators involved in darolutamide resistance.

Main Methods:

  • Utilized cell models of darolutamide-resistant prostate cancer.
  • Investigated the expression and regulation of HSD3B1 (3777) and its upstream regulator NR5A2 (Nuclear Receptor 5A2).
  • Assessed the impact of modulating NR5A2 and HSD3B1 on cellular sensitivity to darolutamide.

Main Results:

  • Overexpression of HSD3B1 was observed in darolutamide-resistant cells and induced by darolutamide treatment and androgen receptor (AR) knockdown.
  • HSD3B1 knockdown increased cellular sensitivity to darolutamide.
  • NR5A2 was up-regulated in resistant cells and induced by darolutamide treatment and AR knockdown.
  • NR5A2 knockdown and inhibition (using ML180) decreased steroidogenic enzyme expression, including HSD3B1, enhancing darolutamide sensitivity.

Conclusions:

  • The NR5A2/HSD3B1 pathway plays a critical role in promoting cellular resistance to darolutamide in prostate cancer.
  • Targeting the NR5A2/HSD3B1 pathway represents a promising therapeutic strategy to overcome darolutamide resistance.
Keywords:
Androgen-deprivation therapyDarolutamideHSD3B1NR5A2Prostate cancer

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