Journal
CANCER RESEARCH
Volume 72, Issue 9, Pages 2176-2182Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-11-3980
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Funding
- Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology)
- Amgen
- Astellas
- AstraZeneca
- Boehringer Ingelheim
- Bristol-Myers Squibb
- Dendreon
- Enzon
- Exelixis
- Genentech
- GlaxoSmithKline
- Medivation
- Merck
- Novartis
- Pfizer
- Roche
- Sanofi-Aventis
- Supergen
- Takeda
- Janssen-Cilag
- Veridex
- Millennium Pharmaceuticals
- Ipsen
- Cancer Research UK
- Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK
- Department of Health [C51/A7401]
- NIHR clinical lectureship
- Welcome Trust
- Prostate Cancer Foundation, Santa Monica, CA
- Prostate Action, London, UK
- Medical Research Council (MRC) UK [G0801473]
- Chief Scientist's Office, Scottish Government
- NHS
- MRC [G0801473] Funding Source: UKRI
- Cancer Research UK [13239] Funding Source: researchfish
- Medical Research Council [G0801473] Funding Source: researchfish
- National Institute for Health Research [CL-2008-22-001] Funding Source: researchfish
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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. Cancer Res; 72(9); 2176-82. (C) 2012 AACR.
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