HER2作为前列腺癌的治疗靶点：跨遗传血统的多组学与空间洞察

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 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. IHC staining was used to detect HER2 expression in primary prostate tissue. We quantified transcript and protein levels of HER levels in PC cell lines by qPCR and ELISA. CellTiter-Glo® assessed cell viability in PC cells treated with anti-HER2 drug. We performed multi-omic analyses using LC-tandem mass spectrometry and LC-PRM mass spectrometry. Biological pathway and network analysis was performed using Qiagen's Ingenuity Pathway Analysis. We validated significantly modulated genes with qPCR. 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. 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). Transcript and protein levels of HER2 were confirmed in PC cells. We observed significantly reduced viability only in HER2-targeted PC cells from Black patients. Systems biology revealed differential pathway and network expression in HER2-targeted PC cells derived from Black men compared with white men. Common significantly modulated genes ERBB2, MYC, MYCN, and TP63 were validated. HER2 and AR immunofluorescence staining diminished 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.