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 model and an in-vivo model of CRPC. Results: We report that in multiple CRPC transcriptome cohorts the GO Cellular Response to Heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely NXP800 (formerly CCT361814), in PCa. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant PCa models. Conclusions: Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development.