Abstract A075: HER2 as an Ancestry-associated Therapeutic Target in Prostate Cancer

Abstract INTRODUCTION: Patients with prostate cancer (PC) initially respond to androgen deprivation therapy. However, relapse is lethal. For this reason, inhibiting androgen-independent signaling pathways—such as human epidermal growth factor receptor 2 (HER2)—is a promising area of investigation. HER2 overexpression in PC tumors correlates with worse prognosis, but HER2 has not been sufficiently evaluated in Black men. We hypothesize that unique ancestry-associated multi-omic molecular signatures are modulated with anti-HER2 drug targeting. METHODS: Using RNA sequencing, we quantified HER2/ERBB2 in primary patient tissue and correlated with quantified ancestry estimates with genotyping. Immunohistochemistry staining was used to detect HER2 expression in primary prostate tissue. We quantified HER2/ERBB2 levels in a diverse panel of PC cell lines by qPCR. CellTiter-GloÒ assessed cell viability in PC cells treated with anti-HER2 drug trastuzumab. We performed multi-omic analyses using liquid chromatography-tandem mass spectrometry and liquid chromatography with parallel reaction monitoring mass spectrometry. Biological pathway and network analysis was performed using Qiagen’s Ingenuity Pathway Analysis. We performed immunofluorescence staining of HER2 and androgen receptor (AR) in treated vs. untreated PC cell lines. To resolve the spatial dynamics of ERBB2 and AR in ancestry genotyped patient-derived xenografts (PDXs), we utilized the 10x Genomics Xenium In Situ spatial transcriptomics platform using Xenium’s 377-gene Human Multi-Tissue Cancer panel. RESULTS: We detected moderate correlation with HER2/ERBB2 and West African genetic ancestry (WAA) in primary prostate tissue in a cohort of Black men (n=36). We detected HER2-positive scores in 70% of primary PC tissue in a separate cohort of Black men (n=10). HER2/ERBB2 transcript levels were confirmed in PC cells. We observed significantly reduced viability only in PC cells from Black patients treated with trastuzumab. Systems biology revealed differential pathway and network expression in PC cells derived from Black men compared with white men when treated with trastuzumab. Immunofluorescence demonstrated markedly diminished HER2 staining, coinciding with a reduction in nuclear AR signal intensity with HER2 drug targeting. Spatial transcriptomic analysis revealed that the ERBB2 and AR transcript burden per tumor area were significantly higher in a PDX developed from a Black patient (58% WAA) compared to a PDX developed from a white patient (0% WAA). CONCLUSIONS: Thorough evaluation of the molecular mechanisms by which HER2 overexpression confers tumor progression and treatment-resistance will provide the foundation to address high-risk PC with precision medicine. By leveraging the unique characteristics of HER2-positive tumors, an additional oncogenic pathway can be therapeutically targeted which will have a major impact in reducing progression to metastasis and reducing mortality. Citation Format: Leanne Woods-Burnham, Nicole Mavingire, Abdulrahman M. Dwead, Joy Solomon, Janelle Moore, Moyinoluwa Adeniyi, Odunayo Oluokun, Jabril R. Johnson, Estefania Labanca, Peter Shepherd, Mya Walker, Isaiah Sailors, Serene Dowiri, Greisha Ortiz-Hernandez, Jillian C. McDonough, Diana LeVasseur, Jazlyn Farlough, Justin Tran, Frank Myers, Fornati Bedell, Zhirong Yin, Rachel Martini, Melissa B. Davis, Clayton C. Yates, K. Sean Kimbro, Rick A. Kittles, Tanya Dorff, Cristina Magi-Galluzzi, Soroush Rais-Bahrami, Firas Kobeissy, Yehia Mechref. HER2 as an Ancestry-associated Therapeutic Target in Prostate Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A075.