title: Conversion of abiraterone to D4A drives anti-tumour activity in prostate cancer.
abstract: Prostate cancer resistance to castration occurs because tumours acquire the metabolic capability of converting precursor steroids to 5α-dihydrotestosterone (DHT), promoting signalling by the androgen receptor and the development of castration-resistant prostate cancer. Essential for resistance, DHT synthesis from adrenal precursor steroids or possibly from de novo synthesis from cholesterol commonly requires enzymatic reactions by 3β-hydroxysteroid dehydrogenase (3βHSD), steroid-5α-reductase (SRD5A) and 17β-hydroxysteroid dehydrogenase (17βHSD) isoenzymes. Abiraterone, a steroidal 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor, blocks this synthetic process and prolongs survival. We hypothesized that abiraterone is converted by an enzyme to the more active Δ(4)-abiraterone (D4A), which blocks multiple steroidogenic enzymes and antagonizes the androgen receptor, providing an additional explanation for abiraterone's clinical activity. Here we show that abiraterone is converted to D4A in mice and patients with prostate cancer. D4A inhibits CYP17A1, 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, competitive androgen receptor antagonism by D4A is comparable to the potent antagonist enzalutamide. D4A also has more potent anti-tumour activity against xenograft tumours than abiraterone. Our findings suggest an additional explanation-conversion to a more active agent-for abiraterone's survival extension. We propose that direct treatment with D4A would be more clinically effective than abiraterone treatment.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Zhenfei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bishop
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Alyamani
authors.affiliation: 1] Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: 1] Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.affiliation: Department of Laboratory Medicine, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Dustin
authors.initials: D
authors.lastname: Bunch
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Upadhyay
authors.affiliation: 1] Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Auchus
authors.affiliation: 1] Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [2] Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA [3] Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Nima
authors.initials: N
authors.lastname: Sharifi
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D059002:Androgen Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000728:Androgens / Q000096:biosynthesis / Q000378:metabolism; D000736:Androstenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001549:Benzamides; D053898:Biosynthetic Pathways / Q000187:drug effects; D001711:Biotransformation; D002455:Cell Division; D002843:Chromatin / Q000378:metabolism; D013196:Dihydrotestosterone / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy; D011944:Receptors, Androgen / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D058891:5-alpha Reductase Inhibitors; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000736:Androstenes; D001549:Benzamides; D002843:Chromatin; D009570:Nitriles; D011944:Receptors, Androgen; C000600172:delta4-abiraterone; D013196:Dihydrotestosterone; D010669:Phenylthiohydantoin; C540278:enzalutamide; D015096:3-Hydroxysteroid Dehydrogenases; D013254:Steroid 17-alpha-Hydroxylase; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C089740:abiraterone