IRE1 activity is prognostic in localised and metastatic prostate cancer and affects epithelial lineage states.

Prostate cancer (PCa) is an androgen receptor (AR) driven, high-incidence disease significantly contributing to cancer mortality. To improve treatment outcomes for patients at high risk of metastasis, PCa is in need of better risk stratification at diagnosis. The unfolded protein response (UPR) is an AR-dependent process. However, the impact of the UPR transducer IRE1 on AR-dependent biology and acquired treatment resistance has not been defined. We use pre-clinical models of stress response to describe the impact of IRE1 activity loss on multiple PCa stages and demonstrate its involvement with poor prognosis (RB1 loss), and cell lineage determination (club-like phenotypes). Integrating clinical transcriptomic datasets, we chart IRE1 activity throughout PCa evolution and develop an IRE1 activity signature (IRE1sig1.0) reflecting both tumoral and micro-environmental stress responses. IRE1sig1.0 correlates with tumoral identity, and prognosticates localised and metastatic disease independently from AR activity. Using IRE1sig1.0 as a tool may inform ARSI suitability and guide IRE1 modulation as a novel combination therapeutic in prostate cancer.