Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in and -Mutated Prostate Cancer.

Deletions or mutations in and tumor suppressor genes have been linked to lineage plasticity in therapy-resistant prostate cancer. Fusion-driven overexpression of the oncogenic transcription factor is observed in approximately 50% of all prostate cancers, many of which also harbor and alterations. However, the role of ERG in lineage plasticity of /-altered tumors is unclear. Understanding the collective effect of multiple mutations within one tumor is essential to combat plasticity-driven therapy resistance. We generated a -negative/-mutated/-overexpressing mouse model of prostate cancer and integrated RNA-sequencing with ERG chromatin immunoprecipitation-sequencing (ChIP-seq) to identify pathways regulated by ERG in the context of / alteration. We investigated ERG-dependent sensitivity to the antiandrogen enzalutamide and cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib in human prostate cancer cell lines, xenografts, and allografted mouse tumors. Trends were evaluated in TCGA, SU2C, and Beltran 2016 published patient cohorts and a human tissue microarray. Transgenic expression in mice blocked / alteration-induced decrease of AR expression and downstream luminal epithelial genes. ERG directly suppressed expression of cell cycle-related genes, which induced RB hypophosphorylation and repressed E2F1-mediated expression of mesenchymal lineage regulators, thereby restricting adenocarcinoma plasticity and maintaining antiandrogen sensitivity. In ERG-negative tumors, CDK4/6 inhibition delayed tumor growth. Our studies identify a previously undefined function of ERG to restrict lineage plasticity and maintain antiandrogen sensitivity in /-altered prostate cancer. Our findings suggest ERG fusion as a biomarker to guide treatment of /-altered, -intact prostate cancer. .