Abstract In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR)-dependence due to lineage plasticity, which has become more prevalent, leads to clinically highly aggressive tumors with few therapeutic options and is mechanistically poorly defined. To identify the master transcription factors (TFs) of CRPC in a subtype-specific manner, we derived and collected 29 metastatic human prostate cancer organoids and cell lines, and generated ATAC-seq, RNA-seq and DNA sequencing data. We identified four subtypes and their master TFs using novel computational algorithms: AR-dependent; Wnt-dependent, driven by TCF; neuroendocrine, driven by ASCL1 and NEUROD1 and stem cell-like (SCL), driven by the AP-1 family. The transcriptomic signatures of these four subtypes enabled the classification of 370 patients. We find that AP-1 co-operates with the inhibitable YAP/TAZ/TEAD pathway in the SCL subtype, the second most common group of CRPC tumors after AR-dependent. Together, this molecular classification reveals new drug targets and can potentially guide therapeutic decisions.

Chromatin accessibility profiles of castration-resistant prostate cancers reveal novel subtypes and therapeutic vulnerabilities