Localized high-risk prostate cancer harbors an androgen receptor activity–low subpopulation susceptible to HER2 inhibition
Scott Wilkinson, … , Fatima Karzai, Adam G. Sowalsky
Scott Wilkinson, … , Fatima Karzai, Adam G. Sowalsky
Published September 4, 2025
Citation Information: J Clin Invest. 2025;135(22):e189900. https://doi.org/10.1172/JCI189900.
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Clinical Research and Public Health Genetics Oncology

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

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 levels in pretreatment biopsy specimens. The inverse AR-HER2 relationship recurred across data sets 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.

Authors

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

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Figure 1

Integrated molecular landscape of prostate tumors prior to neoadjuvant-intense ADT.

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Integrated molecular landscape of prostate tumors prior to neoadjuvant-i...
(A) Schematic of workflow in which LCM and RNA-Seq of tumor foci from image-guided baseline biopsy specimens (left) were used to assess gene expression differences that track with posttreatment pathologic tumor volumes (right). (B) Distribution of RCB (1 row per patient) plotted on a logarithmic x-axis with a pseudocount (cm3 + 1). ER, exceptional responders (residual tumor volumes <0.05 cm3). INR patients had residual tumor volumes ≥0.05 cm3. (C) Principal component (PC) analysis of 147 baseline tumor foci transcriptomes. Each dot is colored by patient, with squares representing foci from INR patients and circles representing foci from ER patients. (D) Heatmap and oncoprint depicting molecular and histologic features of baseline tumors. Each column represents 1 laser-capture microdissected tumor focus subjected to whole-transcriptome sequencing. Identical values are given to IHC profiling performed on a single tissue that was subdivided for sequencing. Black bars at the bottom indicate multiple samples from the same patient. Samples are ranked from left to right by patient-level RCB volumes. Heatmap of IHC depicts histology intensity scores reported by Wilkinson et al. (22). ADPC, adenocarcinoma; NEPC, neuroendocrine; SCL, stem cell-like; WNT, Wnt-dependent.