Targeting heat shock machinery to abrogate persistent androgen receptor signalling in lethal prostate cancer.

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 strategies targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is targeting heat shock proteins critical to AR functional activity. Herein, we report that in multiple advanced PCa transcriptome cohorts the GO Cellular Response to Heat signature associates with AR signaling and worse clinical outcomes. We demonstrate that targeting the heat shock factor 1 (HSF1) pathway, central to cellular stress, with an inhibitor in clinical development (CCT361814/NXP800) decreases HSP70 expression and activates the unfolded protein response, inhibiting AR and E2F mediated activity as well as the growth of treatment resistant PCa models. Overall, CCT361814/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