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 models limits effective drug screening. In this study, we introduce ACRJ-PC28, a novel Afro-Caribbean prostate cancer cell line, and evaluate its responses to five anticancer drugs (docetaxel, cabazitaxel, abiraterone, olaparib, and enzalutamide) and betaine. We compare these responses with those of established prostate cancer cell lines from Black (MDA-PCA-2b) and White (DU-145 and PC-3) donors using three distinct viability assays. We observed ancestry-dependent drug sensitivities: abiraterone showed remarkable selectivity for ACRJ-PC28 (IC50 = 1.10 μmol/L), being 4.6- to 13.1-fold more potent than in other cell lines, whereas enzalutamide demonstrated pronounced racial differences, being 3 to 5 times less effective in cell lines from Black donors (IC50 = 206 μmol/L for ACRJ-PC28; 104 μmol/L for MDA-PCA-2b) versus cell lines from White donors (IC50 = 37 μmol/L for PC-3; 48 μmol/L for DU-145). RNA sequencing analysis revealed consistent underexpression of TNF family genes, particularly TNFRSF14, in prostate cancer 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 prostate cancer respond better to this therapy. This aligns with its neuroendocrine phenotype in the source patient, who succumbed within 1 year despite androgen deprivation therapy. Our findings suggest that incorporating diverse prostate cancer models in preclinical screening could guide personalized treatment strategies for Black patients who experience disproportionate prostate cancer mortality by identifying ancestry-specific drug vulnerabilities that inform optimal therapeutic combinations.

Significance: This study introduces ACRJ-PC28, the first Afro-Caribbean prostate cancer cell line, revealing ancestry-dependent drug sensitivities that could explain differential clinical outcomes. The findings demonstrate critical gaps in current preclinical models and support incorporating diverse cell lines to develop personalized treatment strategies for underrepresented populations experiencing disproportionate cancer mortality.