ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is
Jordan E Vellky1,2, Brenna J Kirkpatrick1, Lisa C Gutgesell1
1Department of Pathology, The University of Illinois at Chicago, Chicago, Illinois.
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.
Insights
Overexpression of ERBB3 (HER3) in castration-sensitive prostate cancer (CSPC) is linked to advanced disease and resistance to enzalutamide. Targeting HER3 may improve treatment sensitivity in CSPC patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Castration-sensitive prostate cancer (CSPC) has a good prognosis, but progression to castration-resistant prostate cancer (CRPC) significantly reduces survival rates.
- Current combination treatment strategies for preventing recurrence are often used in biomarker-unselected patients.
- Identifying predictive biomarkers in CSPC is crucial for guiding therapeutic strategies and improving patient outcomes.
Purpose of the Study:
- To identify a predictive biomarker in castration-sensitive prostate cancer (CSPC) that indicates progression on standard-of-care therapy.
- To investigate the role of ERBB3 (HER3) overexpression in CSPC and its association with disease progression and treatment resistance.
Main Methods:
- Targeted deep sequencing and immunostaining were performed on patient cohorts.
- Bioinformatic analyses integrated RNA sequencing data from multiple databases.
- Functional experiments utilized neutralizing antibodies and ectopic HER3 overexpression in prostate cancer cell lines.
Main Results:
- ERBB3 overexpression was identified in diverse CSPC patient populations and associated with advanced disease at diagnosis.
- ERBB3 expression correlated with androgen response pathways despite low androgen levels, particularly in Black/African American men.
- HER3 promoted enzalutamide resistance in cell line models, and HER3-targeted therapy resensitized resistant cell lines.
Conclusions:
- ERBB3 overexpression in CSPC is linked to high androgen receptor signaling despite low androgen levels.
- HER3 plays a mechanistic role in enzalutamide resistance.
- ERBB3 can serve as a biomarker to stratify patients for intensified therapy in CSPC, including direct HER3 targeting to enhance sensitivity to androgen-targeted therapies.
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:23Abnormal Proliferation
01:20The Retinoblastoma Gene
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
02:38The Ras Gene
Ras is a...