ArticleThe Journal of clinical investigation2018
HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 52 citations in OpenAlex.
- Circulating and Intratumoral Adrenal Androgens Correlate with Response to Abiraterone in Men with Castration-Resistant Prostate Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2021Trial
- 3beta-HSD1-mediated steroid back-conversion maintains androgen signaling in prostate cancer.Molecular cancer research : MCR · 2026Article
- Pyridine indole hybrids as novel potent CYP17A1 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Novel hormone therapies for advanced prostate cancer: Understanding and countering drug resistance.Journal of pharmaceutical analysis · 2025Review
- HSD3B1, prostate cancer mortality and modifiable outcomes.Nature reviews. Urology · 2025Review
- Survival of men with metastatic hormone-sensitive prostate cancer and adrenal-permissive HSD3B1 inheritance.The Journal of clinical investigation · 2024Article
- Adrenal-Permissive Germline HSD3B1 Allele and Prostate Cancer Outcomes.JAMA network open · 2024Article
- Non-steroidal CYP17A1 Inhibitors: Discovery and Assessment.Journal of medicinal chemistry · 2023Review
- Adrenal Steroids and Resistance to Hormonal Blockade of Prostate and Breast Cancer.Endocrinology · 2023Review
- Is androgen receptor activity in metastatic prostate cancer a good biomarker for bipolar androgen therapy?The Journal of clinical investigation · 2022Article
- The clinical efficacy and limitations of dutasteride-regulated abiraterone metabolism in abiraterone-resistant patients: a prospective single-arm clinical trial in Chinese patients.Translational andrology and urology · 2022Article
- Management of prostate cancer by targeting 3βHSD1 after enzalutamide and abiraterone treatment.Cell reports. Medicine · 2022Article
- Regulatory genes in the androgen production, uptake and conversion (APUC) pathway in advanced prostate cancer.Endocrine oncology (Bristol, England) · 2022Review
- Review
- Hormonal Therapy for Prostate Cancer.Endocrine reviews · 2021Review
- Article
- Volume matters and intensification is needed: emerging trends in the management of advanced prostate cancer.Drugs in context · 2021Review
- Androgen Receptor Signaling Pathway in Prostate Cancer: From Genetics to Clinical Applications.Cells · 2020Review
- Germline HSD3B1 Genetics and Prostate Cancer Outcomes.Urology · 2020Review
- Exposure-response analyses of abiraterone and its metabolites in real-world patients with metastatic castration-resistant prostate cancer.Prostate cancer and prostatic diseases · 2020Observational
Corrections and comments
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Authors and funding
20 authors at 7 institutions in 2 countries.
Funding
Abstract
backgroundA common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3βHSD1 to multiple steroidal metabolites, including 3-keto-5α-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5α-abiraterone synthesis in patients.
methodsFirst, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5α-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics.
resultsPatients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5α-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002).
conclusionIncreased generation of 3-keto-5α-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition.
fundingProstate Cancer Foundation Challenge Award, National Cancer Institute.
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