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.
Written by:
Richards J, Lim AC, Hay CW, Taylor AE, Wingate A, Nowakowska K, Pezaro C, Carreira S, Goodall J, Arlt W, McEwan IJ, de Bono JS, Attard G. Are you the author?
Section of Medicine, The Institute of Cancer Research; The Royal Marsden NHS Foundation Trust, Sutton, Surrey; School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen; and Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, United Kingdom.
Reference: Cancer Res. 2012 May 1;72(9):2176-82.
doi: 10.1158/0008-5472.CAN-11-3980
PubMed Abstract
PMID: 22411952
UroToday.com Prostate Cancer Section