Identifying critical pathways governing disease progression is essential for accurate prognosis and effective therapy. We developed a broadly applicable and novel systems-level gene discovery strategy. This approach focused on constitutively active androgen receptor (AR) splice variant-driven pathways as representative of an intractable mechanism of prostate cancer (PC) therapeutic resistance. We performed a meta-analysis of human prostate samples using weighted gene co-expression network analysis combined with experimental AR variant transcriptome analyses. An AR variant-driven gene module that is upregulated during human PC progression was identified. We filtered this module by identifying genes that functionally interacted with AR variants using a high-throughput synthetic genetic array screen in  Schizosaccharomyces pombe  This strategy identified seven AR variant-regulated genes that also enhance AR activity and drive cancer progression. Expression of the seven genes predicted poor disease-free survival in large independent PC patient cohorts. Pharmacologic inhibition of interacting members of the gene set potently and synergistically decreased PC cell proliferation. This unbiased and novel gene discovery strategy identified a clinically relevant, oncogenic, interacting gene hub with strong prognostic and therapeutic potential in PC.