局部高危前列腺癌存在对HER2抑制敏感的雄激素受体活性低的亚群。

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

作者信息

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

机构信息

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

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

出版信息

J Clin Invest. 2025 Sep 4. doi: 10.1172/JCI189900.

DOI:10.1172/JCI189900

PMID:40906535

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.

摘要

背景

尽管进行了新辅助雄激素剥夺治疗（ADT），局限性高危前列腺癌（PCa）仍常复发。我们试图确定可预测病理反应并揭示可靶向弱点的基线分子程序。

方法

我们对37例患者48个MRI可见病变中的147个活检病灶进行了分析，这些患者在接受6个月的ADT加恩杂鲁胺及根治性前列腺切除术之前。前列腺切除术中的残余癌负担（RCB）是主要结局。分析纳入了基线和治疗后组织中的PTEN缺失、TMPRSS2:ERG状态以及HER2/雄激素受体（AR）免疫组化。在一个外部转录队列（n = 121）中以及通过在一个独立队列（n = 61）中进行多重免疫染色对结果进行了评估。功能试验检测了ERBB2附近对恩杂鲁胺有反应的增强子以及对HER2抑制的敏感性。

结果

一个基线HER2相关转录程序与较高的RCB相关，且与AR活性呈负相关，独立于PTEN和ERG。特别有效的反应者在预处理活检中HER2蛋白含量较低。AR-HER2的负相关关系在各数据集和多重免疫染色中反复出现，这揭示了同时存在的AR高/HER2低和HER2高/AR低亚群。恩杂鲁胺抑制AR介导的对ERBB2的抑制作用。治疗前存在的HER2高、AR低细胞对ADT有抵抗，但对HER2抑制剂敏感；将HER2抑制剂与恩杂鲁胺联合使用可增加肿瘤细胞杀伤。这些发现在外周队列和正交试验中得到了重现。