ERBB3 overexpression is enriched in diverse patient populations with castration-sensitive prostate cancer and is associated with a unique AR activity signature

  • Clin Cancer Res. 2024 Feb 2. doi: 10.1158/1078-0432.CCR-23-2161.
Jordan E Vellky  1 ,  Brenna J Kirkpatrick  1 ,  Lisa C Gutgesell  1 ,  Mathias Morales  2 ,  Ryan M Brown  1 ,  Yaqi Wu  1 ,  Mark Maienschein-Cline  1 ,  Lucia D Notardonato  1 ,  Michael S Weinfeld  1 ,  Ryan H Nguyen  1 ,  Eileen Brister  1 ,  Maria Sverdlov  1 ,  Li Liu  1 ,  Ziqiao Xu  1 ,  Steven Kregel  3 ,  Larisa Nonn  1 ,  Donald J Vander Griend  1 ,  Natalie M Reizine  1
Affiliations
  • 1. University of Illinois at Chicago, Chicago, IL, United States.
  • 2. University of Illinois at Chicago, United States.
  • 3. Loyola University Chicago, Maywood, IL, United States.
PMID: 38306015 DOI: 10.1158/1078-0432.CCR-23-2161
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.

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