Abstract 3592: Androgens interfere with enzalutamide agonism of mutant F876L androgen receptor

Multiple lines of evidence demonstrate that castration-resistant prostate cancers (CRPCs) remain reliant on androgens that activate the androgen receptor (AR). Treatment with the novel anti-androgen enzalutamide improves both progression-free and overall survival in CRPC patients (Beer, 2014, Scher, 2012). However, progression is universal. Recently, F876L mutations in the AR ligand binding domain have been described (Balbas, 2013, Korpal, 2013, Joseph, 2013). This mutation confers resistance to enzalutamide treatment and in some cases converts enzalutamide to an AR agonist in pre-clinical studies (Balbas, 2013, Korpal, 2013, Joseph, 2013). Clinical studies demonstrate that ∼10% of patients harbor F876L mutations after treatment with novel anti-androgens (Joseph, 2013). However, anti-androgen withdrawal effects (PSA responses) after discontinuing enzalutamide are rarely seen clinically (Rodriguez-Vida, 2014). An enzalutamide-resistant cell line was developed after chronic treatment of LNCaP cells in vivo. We found that this resistant cell line was dependent on AR expression for survival and that this cell line harbored an AR F876L mutation. When these resistant cells were cultured in complete serum, enzalutamide treatment did not lead to agonistic effects. However, enzalutamide treatment of these resistant cells or cell lines with ectopic expression of AR F876L cultured in androgen-depleted serum led to a significant agonistic effect - an effect that was attenuated by the addition of androgens to culture. Finally, prior work and our own demonstrated that F876L mutant and wild-type AR activate similar pathways (Joseph, 2013). Therefore, we determined if suppression of previously described transcriptional co-activators of wild-type AR also blocked AR F876L function. We found several targetable AR co-activators that met that standard. 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 critical AR transcriptional co-activators is a promising strategy to suppress mutant AR F876L function irrespective of whether the AR agonist is androgens or enzalutamide. Citation Format: Daniel Coleman, Katy Van Hook, Robert Lisac, Carly King, Nicholas Wang, Jacob Schwartzman, Martin Gleave, Lina Gao, Joshua Urrutia, Laura Heiser, Joshi J. Alumkal. Androgens interfere with enzalutamide agonism of mutant F876L androgen receptor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3592. doi:10.1158/1538-7445.AM2015-3592