Loss of NCOA6 protein causes aggressive prostate cancer with EGFR overexpression and dependency.

Loss of tumor suppressors can drive carcinogenesis while simultaneously creating actionable therapeutic vulnerabilities. Epidermal growth factor receptor (EGFR) is frequently overexpressed in prostate cancer (PCa), yet EGFR inhibitors have shown limited clinical benefit, and the basis for this variability remains unclear. Here, analysis of 1,719 human PCa specimens reveals frequent downregulation of the nuclear receptor coactivator 6 (NCOA6), particularly in metastatic disease. Genetic loss of NCOA6 accelerates tumor growth in human PCa xenografts, induces prostate tumorigenesis in mice, and cooperates with Pten haploinsufficiency to drive aggressive metastatic PCa. Mechanistically, NCOA6 forms a repressive complex with nuclear transcription factor Y (NFY) at a distal EGFR enhancer, blocking p300 recruitment and limiting EGFR transcription. Loss of NCOA6 derepresses EGFR, causing EGFR overexpression and rendering both androgen-sensitive and castration-resistant PCa highly dependent on EGFR signaling and exquisitely sensitive to EGFR inhibition. These findings identify NCOA6 as a potent tumor suppressor and a clinically relevant biomarker to stratify PCa patients most likely to benefit from EGFR-targeted therapy.