BET Bromodomain Inhibitors Enhance Efficacy and Disrupt Resistance to AR Antagonists in the Treatment of Prostate Cancer
Menée sur des lignées cellulaires de cancer de la prostate ayant développé une résistance à l'enzalutamide, cette étude suggère l'intérêt thérapeutique d'une stratégie combinant un inhibiteur de BET et un antagoniste du récepteur des androgènes
Next generation anti-androgen therapies such as enzalutamide and abiraterone have had a profound impact on the management of metastatic castration-resistant prostate cancer (mCRPC). However, mCRPC patients invariably develop resistance to these agents. Here, a series of clonal cell lines were developed from enzalutamide-resistant prostate tumor xenografts to study the molecular mechanism of resistance and test their oncogenic potential under various treatment conditions. Androgen receptor (AR) signaling was maintained in these cell lines which acquired potential resistance mechanisms including expression of AR-variant 7 (AR-v7) and glucocorticoid receptor (GR). BET bromodomain inhibitors were shown previously to attenuate AR signaling in mCRPC; here, we demonstrate the efficacy of BET inhibitors in enzalutamide-resistant prostate cancer models. AR antagonists, enzalutamide and ARN509 exhibit enhanced prostate tumor growth inhibition when combined with BET inhibitors, JQ1 and OTX015, respectively. Taken together, these data provide a compelling pre-clinical rationale to combine BET inhibitors with AR antagonists to subvert resistance mechanisms. Implications: Therapeutic combinations of BET inhibitors and AR antagonists may enhance the clinical efficacy in the treatment of mCRPC.