Localized high-risk prostate cancer harbors an androgen receptor activity-low subpopulation susceptible to HER2 inhibition

Scott Wilkinson; Anson T. Ku; Rosina T. Lis; Isaiah M. King; Daniel Low; Shana Y. Trostel; John R. Bright; Nicholas T. Terrigino; Anna Baj; Emily R. Summerbell; Kayla E. Heyward; Sumeyra Kartal; John M. Fenimore; Chennan Li; Cassandra Singler; BaoHan Vo; Caroline S. Jansen; Huihui Ye; Nichelle C. Whitlock; Stephanie A. Harmon; Nicole V. Carrabba; Rayann Atway; Ross Lake; David Y. Takeda; Haydn T. Kissick; Peter A. Pinto; Peter L. Choyke; Baris Turkbey; William L. Dahut; Fatima Karzai; Adam G. Sowalsky

doi:10.1172/JCI189900

¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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¹Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, United States of America

²Office of Intramural Research, National Institutes of Health, Bethesda, United States of America

³Department of Urology, Emory University School of Medicine, Atlanta, United States of America

⁴5Department of Pathology and Department of Urology, University of California Los Angeles, Los Angeles, United States of America

⁵Molecular Imaging Branch, National Cancer Institute, Bethesda, United States of America

⁶Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, United States of America

⁷Urologic Oncology Branch, National Cancer Institute, Bethesda, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI189900.
Copyright © 2025, Wilkinson et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 4, 2025 - Version history

BACKGROUND. Localized high-risk prostate cancer (PCa) often recurs despite neoadjuvant androgen deprivation therapy (ADT). We sought to identify baseline molecular programs that predict pathologic response and reveal targetable vulnerabilities.

METHODS. We profiled 147 biopsy foci from 48 MRI-visible lesions in 37 patients before 6 months of ADT plus enzalutamide and radical prostatectomy. Residual cancer burden (RCB) at prostatectomy was the primary outcome. Analyses incorporated PTEN loss, TMPRSS2:ERG status, and HER2/androgen receptor (AR) immunohistochemistry on baseline and posttreatment tissues. Findings were evaluated in an external transcriptional cohort (n = 121) and by multiplex immunostaining in an independent cohort (n = 61). Functional assays tested enzalutamide-responsive enhancers near ERBB2 and sensitivity to HER2 inhibition.

RESULTS. A baseline HER2-associated transcriptional program correlated with higher RCB and inversely with AR activity, independent of PTEN and ERG. Exceptional responders had lower HER2 protein in pretreatment biopsies. The inverse AR-HER2 relationship recurred across datasets and multiplex immunostaining, which revealed coexisting AR-high/HER2-low and HER2-high/AR-low subpopulations. Enzalutamide inhibited AR-mediated repression of ERBB2. HER2-high, AR-low cells present before therapy resisted ADT yet were sensitive to HER2 inhibitors; combining HER2 inhibitors with enzalutamide increased tumor cell killing. These findings were reproduced in the external cohort and orthogonal assays.

CONCLUSION. Baseline HER2 activity marks intrinsic resistance to neoadjuvant ADT in localized high-risk PCa and identifies a preexisting, targetable AR-low subpopulation. HER2-directed therapy, alone or with AR blockade, warrants clinical evaluation.

TRIAL REGISTRATION. ClinicalTrials.gov registration: NCT02430480.

FUNDING. Prostate Cancer Foundation; Department of Defense Prostate Cancer Research Program; National Institutes of Health.

Version 1 (September 4, 2025): In-Press Preview

Localized high-risk prostate cancer harbors an androgen receptor activity-low subpopulation susceptible to HER2 inhibition

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Localized high-risk prostate cancer harbors an androgen receptor activity-low subpopulation susceptible to HER2 inhibition

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