Patients with advanced prostate cancer who receive androgen deprivation therapy (ADT) almost invariably develop castration-resistant disease. The mechanism of resistance is largely based on synthesis of intratumoral androgens from adrenal precursors, requiring enzymatic action of 3β-hydroxysteroid dehydrogenase/Δ^5→4 isomerase 1 (3β-HSD1), encoded by HSD3B1. A nucleotide polymorphism (1245A>C) in HSD3B1 results in a protein variant with increased steady-state levels and subsequently increased androgen synthesis from extragonadal precursors. Multiple clinical studies have shown that patients with the variant allele have significantly worse outcomes after ADT than those without, indicating that HSD3B1 variant status is a predictive biomarker of shortened ADT response. In addition, inheritance of the HSD3B1 variant is associated with extended responses to 17α-hydroxylase/17,20-lyase (CYP17A1) inhibition with a nonsteroidal agent, adding to evidence of increased tumour dependence on extragonadal androgens in patients who inherited the HSD3B1 variant. However, steroidal drugs with a 3β-hydroxyl, Δ⁵-structure, such as abiraterone, are also metabolized by 3β-HSD1, and 5α-abiraterone, a downstream metabolite, has been shown to activate the androgen receptor, potentially driving cancer progression. These data indicate a potential requirement to modify the treatment framework of patients harbouring variant HSD3B1.

接受雄激素剥夺治疗（ADT）的晚期前列腺癌患者几乎总是会出现去势抵抗性疾病。耐药机制主要基于肾上腺前体的肿瘤内雄激素的合成，需要HSD3B1编码的3β-羟基类固醇脱氢酶/ Δ5 ^→4异构酶1（3β-HSD1）的酶促作用。核苷酸多态性（1245A> C）在HSD3B1结果的蛋白质变体具有增加的稳态水平，并且随后增加从性腺外前体雄激素的合成。多项临床研究表明，具有等位基因变异的患者在ADT后的结局明显比没有等位基因的患者差，这表明HSD3B1变异状态是缩短ADT反应的预测生物标志物。此外，HSD3B1变异的遗传与非甾体类药物对17α-羟化酶/ 17,20-裂解酶（CYP17A1）抑制的延长反应相关，从而增加了继承HSD3B1变异的患者肿瘤对性腺外雄激素依赖性增强的证据。然而，甾体药物与3β-羟基，Δ ⁵ -结构，如阿比特龙，也由3β-HSD1，和5α-阿比特龙，下游代谢物代谢，已显示激活雄激素受体，潜在地驱动癌症进展。这些数据表明可能需要修改携带HSD3B1变异患者的治疗框架。