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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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, demonstrated 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 thisactivity 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.

Original languageEnglish
Pages (from-to)2326-2338
Number of pages13
JournalJournal of Clinical Investigation
Volume127
Issue number6
DOIs
StatePublished - 1 Jun 2017
Externally publishedYes

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