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

PURPOSE: Despite successful clinical management of castration-sensitive prostate cancer (CSPC), the 5-year survival rate for men with castration-resistant prostate cancer 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. EXPERIMENTAL DESIGN: Targeted deep sequencing was performed for the University of Illinois (UI) cohort (n = 30), and immunostaining was performed on a patient tissue microarray (n = 149). Bioinformatic analyses identified pathways associated with biomarker overexpression (OE) in the UI cohort, consolidated RNA sequencing samples accessed from Database of Genotypes and Phenotypes (n = 664), and GSE209954 (n = 68). Neutralizing antibody patritumab and ectopic HER3 OE were utilized for functional mechanistic experiments. RESULTS: We identified ERBB3 OE in diverse patient populations with CSPC, 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 dihydrotestosterone and stable expression of androgen receptor (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 resensitized therapy-resistant prostate cancer cell lines to enzalutamide. CONCLUSIONS: In diverse patient populations with CSPC, 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.

Pseudoduganella danionis sp. nov., isolated from zebrafish (Danio rerio).

One beige-pigmented, Gram-staining-negative, rod-shaped bacterium, strain E3/2T, was isolated from a zebrafish, Daniorerio. Phylogenetic analysis based on nearly full-length 16S rRNA gene sequences showed that the isolate shared 97.7 % 16S rRNA gene sequence similarity to the species Pseudoduganella violaceinigra and between 97.4 to 97.0 % to some species of the genera Duganella and Massilia, including Duganella radicis, Duganella phyllosphaerae, Massilia dura, Massilia lutea, Duganella sacchari, Duganella zoogloeoides, Massiliaalbidiflava and Massilia umbonata. Sequence similarities to all other species were below 97 %. The main cellular fatty acids of the strain were summed feature 3 fatty acids (C16 : 1ω7c/iso-C15 : 0 2-OH), C10 : 0 3-OH, C16 : 0 and C12 : 0. The polyamine pattern of strain E3/2T contained predominantly putrescine and 2-hydroxyputrescine. The major quinone was ubiquinone Q-8. Major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine. Based on phylogenetic, chemotaxonomic, genomic and phenotypic analyses we propose a novel species of the genus Pseudoduganella named Pseudoduganella danionis sp. nov., with strain E3/2T (=LMG 29678T=CCM 8698T) as the type strain.