ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature

Abstract

Purpose: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer (CRPC) is only 32%. Combination treatment strategies to prevent disease recurrence are increasing, albeit in biomarker-unselected patients. Identifying a biomarker in CSPC to stratify patients who will progress on standard-of-care therapy could guide therapeutic strategies. Methods: Targeted deep sequencing was performed for the UI cohort (n=30), and immunostaining was performed on a patient tissue microarray (n=149). Bioinformatic analyses identified pathways associated with biomarker overexpression in the UI cohort, consolidated RNA-seq samples accessed from dbGaP (n=664), and GSE209954 (n=68). Neutralizing antibody Patritumab and ectopic HER3 overexpression were utilized for functional mechanistic experiments. Results: We identified ERBB3 overexpression in diverse CSPC patient populations, where it was associated with advanced disease at diagnosis. Bioinformatic analyses showed a positive correlation between ERBB3 expression and the androgen response pathway despite low DHT and stable expression of AR transcript in Black/African American men. At the protein level, HER3 expression was negatively correlated with intraprostatic androgen in Black/African American men. Mechanistically, HER3 promoted enzalutamide resistance in prostate cancer cell line models and HER3-targeted therapy re-sensitized therapy-resistant prostate cancer cell lines to enzalutamide. Conclusions: In diverse CSPC patient populations, ERBB3 OE was associated with high AR signaling despite low intraprostatic androgen. Mechanistic studies demonstrated a direct link between HER3 and enzalutamide resistance. ERBB3 OE as a biomarker could thus stratify patients for intensification of therapy in castration-sensitive disease, including targeting HER3 directly to improve sensitivity to AR-targeted therapies.