Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer
John D. Norris, Stephanie J. Ellison, Jennifer G. Baker, David B. Stagg, Suzanne E. Wardell, Sunghee Park, Holly M. Alley, Robert M. Baldi, Alexander Yllanes, Kaitlyn J. Andreano, James P. Stice, Scott A. Lawrence, Joel R. Eisner, Douglas K. Price, William R. Moore, William D. Figg, Donald P. McDonnell
John D. Norris, Stephanie J. Ellison, Jennifer G. Baker, David B. Stagg, Suzanne E. Wardell, Sunghee Park, Holly M. Alley, Robert M. Baldi, Alexander Yllanes, Kaitlyn J. Andreano, James P. Stice, Scott A. Lawrence, Joel R. Eisner, Douglas K. Price, William R. Moore, William D. Figg, Donald P. McDonnell
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Research Article Endocrinology

Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer

Abstract

The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase–selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel’s direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor–bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC.

Authors

John D. Norris, Stephanie J. Ellison, Jennifer G. Baker, David B. Stagg, Suzanne E. Wardell, Sunghee Park, Holly M. Alley, Robert M. Baldi, Alexander Yllanes, Kaitlyn J. Andreano, James P. Stice, Scott A. Lawrence, Joel R. Eisner, Douglas K. Price, William R. Moore, William D. Figg, Donald P. McDonnell

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Figure 5

Activity of CYP17 inhibitors in AR-F876L–expressing cells.

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Activity of CYP17 inhibitors in AR-F876L–expressing cells. (A) LNCaP cel...
(A) LNCaP cells engineered to stably express the AR-F876L enzalutamide–resistant AR mutation were treated with vehicle or (B) 3.0 nM testosterone plus 10 μM of the indicated antagonist for 24 hours. AR target genes were assessed by qPCR, and data are presented as heatmaps. (C) HEK293 cells were transfected with an AR-F876L expression plasmid and treated with the indicated ligands (10 μM antagonist plus vehicle or 0.3 nM testosterone) for 4 hours. High-content imaging was performed on fixed cells that were stained for the AR, phalloidin, and DAPI, and the AR N/C ratio is reported. Error bars represent the SEM from 7 to 9 independent experiments. Letters indicate statistically similar groups (P < 0.05) as determined by 1-way ANOVA analysis followed by Bonferroni’s multiple comparisons test. (D) ChIP analysis was performed in LNCaP-F876L cells treated with vehicle or 1.0 nM testosterone and 10 μM of the indicated antagonist for 4 hours. Error bars represent the SD of triplicate qPCR samples from a representative experiment performed in triplicate.