Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 4:e189900.
doi: 10.1172/JCI189900. Online ahead of print.

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

Scott Wilkinson  1 , Anson T Ku  1 , Rosina T Lis  1 , Isaiah M King  1 , Daniel Low  1 , Shana Y Trostel  1 , John R Bright  1 , Nicholas T Terrigino  1 , Anna Baj  1 , Emily R Summerbell  2 , Kayla E Heyward  1 , Sumeyra Kartal  1 , John M Fenimore  1 , Chennan Li  1 , Cassandra Singler  1 , BaoHan Vo  3 , Caroline S Jansen  3 , Huihui Ye  4 , Nichelle C Whitlock  1 , Stephanie A Harmon  5 , Nicole V Carrabba  1 , Rayann Atway  1 , Ross Lake  6 , David Y Takeda  1 , Haydn T Kissick  3 , Peter A Pinto  7 , Peter L Choyke  5 , Baris Turkbey  5 , William L Dahut  1 , Fatima Karzai  1 , Adam G Sowalsky  1
Affiliations
Free article

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

Scott Wilkinson et al. J Clin Invest. .
Free article

Abstract

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.

Clinicaltrials: gov registration: NCT02430480.

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

Keywords: Genetics; Molecular pathology; Oncogenes; Oncology; Prostate cancer.

PubMed Disclaimer

Update of

Associated data