LAUSR

Abstract Castration-resistant prostate cancer (CRPC) remains a lethal disease despite the introduction of second generation androgen receptor (AR) directed therapies. Resistance to AR directed therapies, such as abiraterone and enzalutamide, emerges through diverse alterations in the AR pathway or transition to aggressive AR-null phenotypes. Although bromodomain and extra-terminal (BET) inhibitor therapies are in current clinical trials for CRPC, understanding of the full spectrum of patient responders is limited by a lack of models for preclincial testing. Thus, the goal of this study was to examine the efficacy of BET inhibitors in a panel of patient-derived models of CRPC, including AR-null and neuroendocrine differentiated tumors that are inherently resistant to AR-directed therapy. To rapidly screen the sensitivity of tumors to BET inhibitors, we used ex vivo cultures of patient-derived xenograft tissue from the MURAL (Melbourne Urological Research Alliance) cohort of patient tumors and treated them with JQ1. Changes in proliferation and apoptosis were measured using histology for Ki67 and cleaved caspase 3. Consistent with previous studies, our results showed that all AR-positive tumors were sensitive to JQ1, with decreases in proliferation and increases in apoptosis. Importantly, this includes tumors from patients who failed abiraterone and/or enzalutamide and have diverse alterations of the AR, including mutations, genomic amplifications and expression of truncated AR variants. Surprisingly, 50% of AR null tumors were just as sensitive to BET inhibitors and AR-positive tumors. This includes tumors with large cell and small cell neuroendocrine histopathology, which are inherently resistant to AR-directed therapies. We also assessed intra-patient heterogeneity by examining tumors from different metastases of the same patient. We observed consistent responses in one patient, but divergent responses in another, likely due to differences in AR status. Collectively, our data show that BET inhibitors are promising treatments for tumors with diverse mechanisms of resistance to AR-directed therapies; however, the responses of AR-null tumors are more heterogeneous. Therefore, further studies to identify biomarkers of responsiveness to BET inhibitors in AR-null and neuroendocrine tumors are warranted.