Abstract
BackgroundIntratumoral steroidogenesis and its potential relevance in castration‐resistant prostate cancer (CRPC) and in cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1)‐inhibitor treated hormone‐naïve and patients with CRPC are not well established. In this study, we tested if substrates for de novo steroidogenesis accumulating during CYP17A1 inhibition may drive cell growth in relevant preclinical models.MethodsPCa cell lines and their respective CRPC sublines were used to model CRPC in vitro. Precursor steroids pregnenolone (Preg) and progesterone (Prog) served as substrate for de novo steroid synthesis. TAK700 (orteronel), abiraterone, and small interfering RNA (siRNA) against CYP17A1 were used to block CYP17A1 enzyme activity. The antiandrogen RD162 was used to assess androgen receptor (AR) involvement. Cell growth was measured by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay. AR‐target gene expression was quantified by reverse transcription polymerase chain reaction (RT‐PCR). Nuclear import studies using cells with green fluorescent protein (GFP)‐tagged AR were performed to assess the potential of precursor steroids to directly activate AR.ResultsPreg and Prog stimulated cell proliferation and AR target gene expression in VCaP, DuCaP, LNCaP, and their respective CRPC sublines. The antiandrogen RD162, but not CYP17A1 inhibition with TAK700, abiraterone or siRNA, was able to block Preg‐ and Prog‐induced proliferation. In contrast to TAK700, abiraterone also affected dihydrotestosterone‐induced cell growth, indicating direct AR binding. Furthermore, Prog‐induced AR translocation was not affected by treatment with TAK700 or abiraterone, while it was effectively blocked by the AR antagonist enzalutamide, further demonstrating the direct AR activation by Prog.ConclusionActivation of the AR by clinically relevant levels of Preg and Prog accumulating in abiraterone‐treated patients may act as a driver for CRPC. These data provide a scientific rationale for combining CYP17A1 inhibitors with antiandrogens, particularly in patients with overexpressed or mutated‐AR.
Highlights
Castration‐resistant prostate cancer (CRPC) continues to rely on androgen receptor (AR) signaling for its growth, evidenced by the majority of patients with castration‐ resistant prostate cancer (CRPC) still responding to novel AR signaling pathway targeted agents
Clinical data have shown that a subgroup of patients with CRPC progressing on abiraterone still responds to enzalutamide,[10] suggesting that the AR signaling axis is still active in these patients despite low circulating androgen levels.[11]
Δ4‐Androstenedione synthesis—which is directly dependent on CYP17A1 activity (Figure S1A)—was effectively blocked in H295R cells with IC50 values of 15.5 (95% confidence interval [CI], 10.4‐23.0) and 67.7 nM for abiraterone and TAK700, respectively (Figure S1B)
Summary
Castration‐resistant prostate cancer (CRPC) continues to rely on androgen receptor (AR) signaling for its growth, evidenced by the majority of patients with CRPC still responding to novel AR signaling pathway targeted agents Both the antiandrogen enzalutamide (Xtandi),[1,2] the specific inhibitor of the steroidogenic enzyme cytochrome P450c17 (encoded by cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17A1]), abiraterone acetate (Zytiga), a 17‐α hydroxylase and 17,20‐lyase specific enzyme inhibitor blocking steroidal synthesis from androgen precursors[3,4] demonstrated survival benefit in patients with CRPC both in the pre‐ and in postdocetaxel treatment settings. To further establish the effects of precursor steroids on AR signaling, AR translocation was evaluated using a fluorescently labeled wild‐type AR
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call