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
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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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 5

Enzalutamide treatment of prostate tumor cells selects for a preexisting subpopulation defined by low AR activity and high HER2 activity.

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Enzalutamide treatment of prostate tumor cells selects for a preexisting...
(A) LNCaP cells were treated with enzalutamide (enz) for 0–3 days and subjected to flow cytometry with antibodies against HER2. HER2 fluorescent intensity is depicted as a histogram from a representative experiment. (B and C) Total HER2 (as MFI) (B) or the top 20th percentile of each individual experiment’s (C) control sample fluorescence was used as a cutoff for measuring subpopulations at the 24- and 72-hour time points. Lines indicate data medians; error bars are 95% CIs (n = 5). Statistical significance was determined by Friedman test with Dunn’s post hoc test. (D) AR ChIP-Seq, H3K27ac ChIP-Seq, and H3K27ac HiChIP profiles of LNCaP cells at the KLK3 (left, shown as a control) and ERBB2 (right) loci in enzalutamide or untreated (DMSO) conditions. (E–I) Single-cell gene expression data from LNCaP cells treated with antiandrogen (E and F) were downloaded and normalized together. (F–H) UMAP projections of each treatment condition individually (F), clustered by differential expression (G), and overlaid, colored by treatment condition (H). (I) Following trajectory and pseudobulk differential expression analysis, statistically significant DEGs (Padj < 0.05) in the “resistant” clusters were analyzed with the Upstream Regulator module of IPA. The 10 most activated and inactivated pathways (with Padj < 0.05) are shown.