Freitas Pedro F S, Abdshah Alireza, McKay Rana R, Sharifi Nima
Desai Sethi Urology Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Nat Rev Urol. 2025 May;22(5):313-320. doi: 10.1038/s41585-024-00953-0. Epub 2024 Nov 14.
Androgen receptor stimulation by testosterone and dihydrotestosterone is crucial for prostate cancer progression. Despite the initial effectiveness of androgen deprivation therapy (ADT), castration-resistant prostate cancer eventually develops in most men. A common germline missense-encoding polymorphism in HSD3B1 increases extra-gonadal androgen biosynthesis from adrenal precursors owing to increased availability of the encoded enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) - hence, it is called the adrenal-permissive enzyme. This mechanism explains the more rapid progression to castration-resistant prostate cancer in men who inherit this allele than in men without it via sustained androgen receptor activation despite ADT. Multiple clinical studies, including data derived from prospective phase III studies, have linked adrenal-permissive allele inheritance to inferior clinical responses to ADT and increased mortality, but reversal is possible with upfront adrenal androgen blockade. The adrenal-permissive allele exhibits divergent frequencies across various groups worldwide, which could contribute to differences in clinical outcomes among these populations. Large-scale data from the Million Veteran Program have shown homozygous HSD3B1 adrenal-permissive allele inheritance to be an independent biomarker of prostate cancer-specific mortality. Together, these observations support the integration of HSD3B1 into germline testing and clinical trials as it might help to identify groups at increased likelihood of benefiting from early, intensified, AR-targeting interventions. Lastly, 3βHSD1 is a promising target for pharmacological inhibition, which enables new strategies for systemic prostate cancer therapy.
睾酮和双氢睾酮对雄激素受体的刺激作用对前列腺癌进展至关重要。尽管雄激素剥夺疗法（ADT）最初有效，但大多数男性最终会发展为去势抵抗性前列腺癌。HSD3B1基因中一种常见的种系错义编码多态性，由于编码的3β-羟基类固醇脱氢酶1（3βHSD1）可用性增加，会增加肾上腺前体的性腺外雄激素生物合成，因此它被称为肾上腺允许酶。这一机制解释了，与未继承该等位基因的男性相比，继承该等位基因的男性尽管接受了ADT，但通过持续的雄激素受体激活，会更快地进展为去势抵抗性前列腺癌。多项临床研究，包括来自前瞻性III期研究的数据，已将肾上腺允许等位基因的遗传与ADT的较差临床反应及死亡率增加联系起来，但通过前期肾上腺雄激素阻断有可能实现逆转。肾上腺允许等位基因在全球不同人群中的频率不同，这可能导致这些人群临床结果的差异。百万退伍军人计划的大规模数据表明，纯合子HSD3B1肾上腺允许等位基因的遗传是前列腺癌特异性死亡率的独立生物标志物。总之，这些观察结果支持将HSD3B1纳入种系检测和临床试验，因为它可能有助于识别更有可能从早期、强化的雄激素受体靶向干预中获益的人群。最后，3βHSD1是一个有前景的药物抑制靶点，这为系统性前列腺癌治疗带来了新策略。
