Androgen content and BET bromodomain proteins influence enzalutamide agonism of mutant F876L androgen receptor.

e16538 Background: One emergent resistance mechanism to medical castration is intratumoral androgen synthesis that activates the androgen receptor (AR). This insight led to the development of the AR antagonist enzalutamide. One enzalutamide resistance mechanism is AR F876L mutations that lead to enzalutamide agonism in some cases. However, mechanisms that contribute to the agonist switch have not been fully clarified, and there are no therapies to block AR F876L. Methods: We usedenzalutamide-resistant cell lines harboring AR F876L mutations to determine mechanisms that contribute to enzalutamide activation of mutant F876L AR. Results: Using these cell line models, we determined that cellular androgen content influences enzalutamide agonism of mutant F876L AR. Further, enzalutamide treatment of AR F876L expressing cell lines recapitulated the effects of androgen activation of F876L AR or wild-type AR. Because the BET bromodomain inhibitor JQ1 was previously shown to block androgen activation of wild-type AR, we tested JQ1 in AR F876L-expressing CRPC models. We determined that JQ1 suppressed androgen or enzalutamide activation of mutant F876L AR and suppressed growth of mutant F876L AR CRPC tumors in vivo, demonstrating a new strategy to treat tumors harboring this mutation. Conclusions: Our data demonstrate that androgens interfere with enzalutamide-induced agonism of F876L mutant AR. Because androgens persist in enzalutamide-resistant CRPC, AR activation by androgens, rather than enzalutamide, may explain why enzalutamide discontinuation does not lead to anti-androgen withdrawal effects clinically. Further, our results provide a cautionary note on therapeutic efforts to deplete androgens concomitantly with enzalutamide treatment as this may accentuate AR agonism by enzalutamide in tumors harboring AR F876L mutations. Finally, targeting BET bromodomain proteins is a promising strategy to suppress mutant AR F876L function irrespective of whether the AR agonist is androgens or enzalutamide.