ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature
©2024 The Authors; Published by the American Association for Cancer Research..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 30(2024), 8 vom: 15. Apr., Seite 1530-1543 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Vellky, Jordan E [VerfasserIn] |
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| Links: |
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| Themen: |
2010-15-3 |
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| Anmerkungen: |
Date Completed 16.04.2024 Date Revised 17.04.2024 published: Print Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-2161 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367953722 |
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| 100 | 1 | |a Vellky, Jordan E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a ERBB3 Overexpression is Enriched in Diverse Patient Populations with Castration-sensitive Prostate Cancer and is Associated with a Unique AR Activity Signature |
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| 500 | |a Date Revised 17.04.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2024 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 700 | 1 | |a Morales, Mathias |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Ryan M |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Yaqi |e verfasserin |4 aut | |
| 700 | 1 | |a Maienschein-Cline, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Notardonato, Lucia D |e verfasserin |4 aut | |
| 700 | 1 | |a Weinfeld, Michael S |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Ryan H |e verfasserin |4 aut | |
| 700 | 1 | |a Brister, Eileen |e verfasserin |4 aut | |
| 700 | 1 | |a Sverdlov, Maria |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Li |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Ziqiao |e verfasserin |4 aut | |
| 700 | 1 | |a Kregel, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Nonn, Larisa |e verfasserin |4 aut | |
| 700 | 1 | |a Vander Griend, Donald J |e verfasserin |4 aut | |
| 700 | 1 | |a Reizine, Natalie M |e verfasserin |4 aut | |
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