Coordinated Activity between AR-V7 and Glucocorticoid Receptor in Castration-Resistant Prostate Cancer

Acquired resistance to androgen receptor signaling inhibition (ARSI) is a major clinical challenge for treating advanced prostate cancer. Both the glucocorticoid receptor (GR) and the androgen receptor (AR) splice variant AR-V7 have independently been identified as drivers of this phenomenon. Their mechanisms of resistance share many common features, including upregulation following ARSI and the ability to bypass AR to regulate canonical AR signaling and restore tumor progression. However, despite the similarities no direct relationship between the two has been investigated. Here, we report a novel endogenous interaction between GR and AR-V7 in prostate cancer cell lines. The interaction is mediated by the conserved D-box motif within the DNA-binding domain of each receptor, suggesting heterodimerization. Furthermore, the interaction is only observed subsequent to ARSI, occurs primarily within the nucleus, and enables GR and AR-V7 to co-occupy the promoter of the canonical AR target gene FKBP5. Robust transcriptome analysis reveals that AR-V7 and GR coordinate to drive a unique gene expression profile enriched for proliferative and anti-apoptotic signaling pathways. Finally, we demonstrate that selective glucocorticoid receptor modulators can effectively disrupt the interaction between GR and AR-V7, indicating a potential therapeutic strategy for the subset of V7/GR dual-positive patients with very poor prognoses.