Novel Afro-Caribbean Prostate Cancer Model Reveals ancestry-specific Drug Vulnerabilities with Therapeutic Implications for Black Patients.

Abstract

In the era of targeted therapeutics, the inadequate representation of Black populations in prostate cancer (PCa) models limits effective drug screening. Here, we introduce ACRJ-PC28, a novel Afro-Caribbean PCa cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses to those of established PCa cell lines from Black (MDA-PCA-2b) and White (DU-145, PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: Abiraterone showed remarkable selectivity for ACRJ-PC28 (IC₅₀ = 1.10 μM), being 4.6-13.1 fold more potent than in other cell lines, while Enzalutamide demonstrated pronounced racial differences, being 3-5 times less effective in cell lines from Black donors (IC₅₀ = 206 μM for ACRJ-PC28; 104 μM for MDA-PCA-2b) versus cell lines from White donors (IC₅₀ = 37 μM for PC-3; 48 μM for DU-145). RNA-seq analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in PCa cells from Black donors correlating with differential drug responses. Despite underexpressing AR, the ACRJ-PC28 line exhibited exceptional sensitivity to Abiraterone, consistent with clinical observations that Black patients with PCa respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within one year despite androgen deprivation therapy. Our findings suggest that incorporating diverse PCa models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate PCa mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations.