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Inhibition of the Androgen Receptor by Mineralocorticoids at Levels Physiologically Achieved in Serum in Patients Treated with Abiraterone Acetate

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Inhibition of the Androgen Receptor by Mineralocorticoids at Levels Physiologically Achieved in Serum in Patients Treated with Abiraterone Acetate Prostate Cancer and Prostatic Disease (2014) 17, 292–299 & 2014 Macmillan Publishers Limited All rights reserved 1365-7852/14 www.nature.com/pcan ORIGINAL ARTICLE Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate W Kim1, JO Jones2, M Diamond3, C Haqq4, A Molina5, EJ Small1 and CJ Ryan1 BACKGROUND: Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells. METHODS: Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen- induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells. RESULTS: Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients. CONCLUSIONS: Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted. Prostate Cancer and Prostatic Disease (2014) 17, 292–299; doi:10.1038/pcan.2014.27; published online 22 July 2014 INTRODUCTION studies of men with CRPC.10,11 Some of the notable adverse Retained androgen receptor (AR) activity despite castrate levels events associated with AA results directly from CYP17A1 inhibition of circulating testosterone (T) is a critical biological hallmark leading to decreased adrenal androgen synthesis with a com- associated with the progression of prostate cancer (PC) to its lethal pensatory rise in adrenocorticotropic hormone production.12,13 form.1 Ongoing androgen biosynthesis via cytochrome P450 17A1 This then leads to markedly increased levels of adrenal steroid (CYP17A1) is one process that contributes to the maintenance of hormones upstream of CYP17A1, most notably precursors of AR activity in castration-resistant prostate cancer (CRPC). CYP17A1, aldosterone with potent mineralocorticoid activity (Figure 1). In a complex of enzymes present in testes, adrenal glands and phase I studies of AA alone, on-treatment serum mineralocorticoid prostatic tissue, is the rate-limiting step in the conversion of levels (specifically corticosterone (CS) and deoxycorticosterone steroid hormones into androgens within these organs, and is most (DOC)) increased 11- to 85-fold over baseline levels, leading to responsible for the remaining circulating androgens in men after classical symptoms associated with mineralocorticoid excess, medical or surgical castration.2–4 In men treated with luteinizing including hypokalemia, hypertension and fluid retention.12,13 hormone-releasing hormone agonists, B10% of baseline T As a result, the subsequent clinical development of AA in all remains due to peripheral conversion of adrenal steroids.5 In trials required concomitant administration of corticosteroids, addition, intracrine CYP17A1 activity is a source of androgen usually prednisone, to mitigate these toxicities by suppressing production leading to higher intratumoral androgen levels the adrenocorticotropic hormone feedback loop. However, compared with serum, and a potential contributor to disease despite the concomitant use of prednisone, many AA-treated progression.6–9 Therefore, CYP17A1 inhibition emerged as a patients in the phase III trials experienced adverse events related therapeutic target in CRPC. to mineralocorticoid excess.10,11 Now that AA has received broad Abiraterone acetate (AA; Zytiga, Janssen Biotech, Horsham, PA, regulatory approval and is widely utilized in the management USA) is a highly selective and potent inhibitor of CYP17A13 that of CRPC, it is relevant to annotate the potential physiologic effects has demonstrated profound clinical impact in pivotal phase III of mineralocorticoids on the AR. The AR, a member of the nuclear 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; 2Department of Molecular Pharmacology, City of Hope, Duarte, CA, USA; 3Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA; 4Atara Biotherapeutics, Westlake Village, CA, USA and 5Janssen Research and Development, Los Angeles, CA, USA. Correspondence: Dr W Kim, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 1600 Divisadero Street, San Francisco, CA 94115, USA. E-mail: [email protected] Received 23 March 2014; revised 27 May 2014; accepted 28 May 2014; published online 22 July 2014 AR inhibition by mineralocorticoids W Kim et al 293 Figure 1. The androgen biosynthesis pathway and the effect of CYP17 inhibition on mineralocorticoid and androgen levels. Abiraterone acetate (AA) inhibits the enzyme responsible for the conversion of pregnenolone to dehydroepiandrosterone, which results in increased production of hormones with mineralocorticoid activity and decreased production of androgens. Figure 2. Fluorescence resonance energy transfer (FRET) with androgens: corticosterone (CS) and deoxycorticosterone (DOC) inhibit androgen receptor (AR) conformational change in the presence of androgens. HEK293 cells stably expressing the CFP-AR-YFP FRET reporter were treated with the indicated compounds. AR folding was quantified as the FRET:donor ratio in cells treated in quadruplicate. Cells were treated with 0.9 nM dihydrotestosterone (DHT) or 2.6 nM testosterone (T) alone, and with the combination of DHT and T for 24 h. The DHT/T combination caused AR folding with greater potency. Cells treated with the combination of DHT and T for 24 h were then treated with CS and DOC at various concentrations for 24 h. CS significantly inhibited AR folding in DHT/T-treated cells at concentrations present in the serum of AA-treated patients. DOC demonstrated inhibition of AR folding, but at concentrations higher than present in the serum of AA-treated patients. AA, abiraterone acetate. & 2014 Macmillan Publishers Limited Prostate Cancer and Prostatic Disease (2014), 292 – 299 AR inhibition by mineralocorticoids W Kim et al 294 Figure 3. Fluorescence resonance energy transfer (FRET) without androgens: corticosterone (CS) and deoxycorticosterone (DOC) demonstrate no significant androgen receptor (AR) agonism in the absence of androgens. Neither CS nor DOC induced AR folding in the absence of androgens, indicating no significant AR agonist activity. hormone receptor superfamily, consists of a large group of ligand- in tissues derived from CRPC patients.18–20 The cells were also treated with related transcription factors that include the progesterone, a range of concentrations of CS and DOC, including those comparable to glucocorticoid and mineralocorticoid receptors.14 Promiscuous serum levels in AA-treated patients. After 24 h of exposure, cells were fixed binding to the AR by the ligands of these related receptors in 4% paraformaldehyde and read in PBS on a monochrometer-based has been demonstrated, albeit with lower affinity than that fluorescence plate reader (Safire, Tecan, San Jose, CA, USA). Each plate 15 contained untransfected, positive and negative controls. FRET:donor ratios of androgens. Whether mineralocorticoids such as CS and (representing the degree of AR folding) were calculated following DOC interact significantly with the AR, and whether potential background subtraction and correction for acceptor (YFP) contribution to downstream biological effects have any bearing on the clinical the FRET signal. efficacy, safety or resistance of AA, is unknown. The aim of this in vitro study is to evaluate the biological effects of mineral- Cell cultures ocorticoids on the AR, at concentrations present in the serum of AA-treated patients. Cell lines selected for in vitro studies were as follows: LAPC4, which expresses wild-type AR;21 LNCaP, which expresses an AR mutant with reduced specificity for DHT;22 and LN-AR, an LNCaP-derived cell line that overexpresses AR and recapitulates some features of CRPC.23 LAPC4 cells MATERIALS AND METHODS were maintained in phenol-red free Roswell Park Memorial Institute 1640 Patients and treatment media supplemented with antibiotics and 10% fetal bovine serum. LNCaP Serum mineralocorticoid levels were obtained from patients treated with and LN-AR cells were maintained in Roswell Park Memorial Institute 1640 AA for a minimum of 28 days on a phase I trial conducted at the University media supplemented with sodium bicarbonate, glutamine, HEPES,
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