NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth
Abstract. Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins critical to AR functional activity. Experimental Design: We first did transcriptome analysis on multiple castration-resistant PCa (CRPC) cohorts to correlate the association between the GO Cellular Response to Heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely NXP800, in models of treatment-resistant PCa. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant mo
