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

被引：5

作者：

Shiota, Masaki ^{[1
,2
]}

Ushijima, Miho ^{[1
]}

Tsukahara, Shigehiro ^{[1
]}

Nagakawa, Shohei ^{[1
]}

Blas, Leandro ^{[1
]}

Takamatsu, Dai ^{[1
]}

Kobayashi, Satoshi ^{[1
]}

Matsumoto, Takashi ^{[1
]}

Inokuchi, Junichi ^{[1
]}

Eto, Masatoshi ^{[1
]}

机构：

[1] Kyushu Univ, Grad Sch Med Sci, Dept Urol, Fukuoka 8128582, Japan

[2] Kyushu Univ, Grad Sch Med Sci, Dept Urol, 3-1-1 Maidashi,Higashi ku, Fukuoka 8128582, Japan

来源：

DRUG RESISTANCE UPDATES | 2023年 / 70卷

关键词：

Androgen-deprivation therapy; Darolutamide; Prostate cancer; ANDROGENS; RECEPTOR;

D O I：

10.1016/j.drup.2023.100990

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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.

引用

页数：5

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