Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer

Deep phenotypic characterisation of castration-resistant prostate cancer metastases and patient-derived xenograft lines was carried out using whole-genome RNA sequencing, gene set enrichment analysis and immunohistochemistry. The analyses revealed five phenotypes based on expression of well-characterised androgen receptor or neuroendocrine genes: androgen receptor-high tumours, androgen receptor-low tumours, amphicrine tumours composed of cells co-expressing androgen receptor and neuroendocrine genes, double-negative tumours, and tumours with small cell or neuroendocrine gene expression without androgen receptor activity. REST activity, which suppresses neuroendocrine gene expression, was lost in the amphicrine and small cell or neuroendocrine xenograft models, and knockdown experiments showed that attenuated REST activity drives the amphicrine phenotype but is not sufficient for conversion to the small cell or neuroendocrine phenotype. A subtype of double-negative tumours with squamous differentiation was identified, and a 26-gene transcriptional signature distinguishing the five phenotypes was generated.