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.
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.
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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Feb 02 [Epub ahead of print]
Jordan E Vellky, Brenna J Kirkpatrick, Lisa C Gutgesell, Mathias Morales, Ryan M Brown, Yaqi Wu, Mark Maienschein-Cline, Lucia D Notardonato, Michael S Weinfeld, Ryan H Nguyen, Eileen Brister, Maria Sverdlov, Li Liu, Ziqiao Xu, Steven Kregel, Larisa Nonn, Donald J Vander Griend, Natalie M Reizine
University of Illinois at Chicago, Chicago, IL, United States., University of Illinois at Chicago, United States., Loyola University Chicago, Maywood, IL, United States.