Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100

Juliet Richards, Ai Chiin Lim, Colin W Hay, Angela E. Taylor, Anna Wingate, Karolina Nowakowska, Carmel Pezaro, Suzanne Carreira, Jane Goodall, Wiebke Arlt, Iain J McEwan, Johann S. de Bono, Gerhardt Attard

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Abstract

Prostate cancer progression can be associated with androgen receptor (AR) mutations acquired following treatment with castration and/or an anti-androgen. 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 co-administration 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 CRPC patients were sufficiently high to activate mutant AR. Mineralocorticoid receptor antagonists, such as spironoloactone and eplerenone that are used to treat side-effects related to mineralocorticoid excess, also bound to and activated signaling through both wild-type and 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. Interestingly, activation of mutant AR by eplerenone was inhibited by MDV3100, bicalutamide or greater concentrations of abiraterone. Therefore, an increase in abiraterone exposure above this threshold could reverse resistance secondary to activation of AR by residual ligands or co-administered drugs. Together, our findings provide a strong rationale for clinical evaluation of combined CYP17A1 inhibition and AR antagonism.
Original languageEnglish
Pages (from-to)2176-2182
Number of pages7
JournalCancer Research
Volume72
Issue number9
Early online date12 Mar 2012
DOIs
Publication statusPublished - 1 May 2012

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Richards, J., Lim, A. C., Hay, C. W., Taylor, A. E., Wingate, A., Nowakowska, K., Pezaro, C., Carreira, S., Goodall, J., Arlt, W., McEwan, I. J., de Bono, J. S., & Attard, G. (2012). Interactions of abiraterone, eplerenone, and prednisolone with wild-type and mutant androgen receptor: a rationale for increasing abiraterone exposure or combining with MDV3100. Cancer Research, 72(9), 2176-2182. https://doi.org/10.1158/0008-5472.CAN-11-3980