title: Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100.
abstract: Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an antiandrogen. Abiraterone, a rationally designed inhibitor of CYP17A1 recently approved for the treatment of docetaxel-treated castration-resistant prostate cancer (CRPC), is often effective, but requires coadministration with glucocorticoids to curtail side effects. Here, we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid-induced activation of mutated AR. We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess, can also bind to and activate signaling through wild-type or mutant AR. Abiraterone inhibited in vitro proliferation and AR-regulated gene expression of AR-positive prostate cancer cells, which could be explained by AR antagonism in addition to inhibition of steroidogenesis. In fact, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide, or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism.
authors.affiliation: Section of Medicine, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Juliet
authors.initials: J
authors.lastname: Richards
authors.forename: Ai Chiin
authors.initials: AC
authors.lastname: Lim
authors.forename: Colin W
authors.initials: CW
authors.lastname: Hay
authors.forename: Angela E
authors.initials: AE
authors.lastname: Taylor
authors.forename: Anna
authors.initials: A
authors.lastname: Wingate
authors.forename: Karolina
authors.initials: K
authors.lastname: Nowakowska
authors.forename: Carmel
authors.initials: C
authors.lastname: Pezaro
authors.forename: Suzanne
authors.initials: S
authors.lastname: Carreira
authors.forename: Jane
authors.initials: J
authors.lastname: Goodall
authors.forename: Wiebke
authors.initials: W
authors.lastname: Arlt
authors.forename: Iain J
authors.initials: IJ
authors.lastname: McEwan
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D001549:Benzamides; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004347:Drug Interactions; D000077545:Eplerenone; D006801:Humans; D008297:Male; D015741:Metribolone / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D011239:Prednisolone / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D000736:Androstenes; D000737:Androstenols; D000813:Anilides; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; D013148:Spironolactone; D015741:Metribolone; D000077545:Eplerenone; C540278:enzalutamide; D011239:Prednisolone; C053541:bicalutamide; C089740:abiraterone