Lineage-specific survival vs proliferative enzalutamide resistance states as potential drivers of prostate cancer disparities

African American (AA) men bear a disproportionate burden of prostate cancer, exhibiting higher incidence and mortality rates than their non-Hispanic White American (NHWA) counterparts. Therapeutic resistance is a major driver of prostate cancer-related mortality, and AA patients often show poorer responses to available treatments. Enzalutamide is a second-generation androgen receptor signaling inhibitor widely used to treat advanced metastatic prostate cancer. To investigate lineage-specific mechanisms of enzalutamide resistance, we generated resistant derivatives of the AA-origin MDAPCa2b and the NHWA-origin LNCaP cell lines by gradually increasing enzalutamide exposure. We then performed RNA sequencing-based transcriptomic profiling and integrated gene set enrichment analysis (GSEA), overrepresentation analysis (ORA), and KEGG pathway analysis. Comparison of Enz-R cells with their respective parental lines identified several resistance-associated differentially expressed genes (DEGs), revealing lineage-specific transcriptional programs. Notably, MDAPCa2b Enz-R cells exhibited a robust survival program characteristic of aggressive, therapy-refractory prostate cancer. Although these cells retained a measurable proliferative capacity, they adopted a persister-like, metabolically minimized state, marked by the coordinated downregulation of oxidative phosphorylation, glycolysis, pentose phosphate pathway, amino acid and tRNA biosynthesis, ribosome biogenesis, and proteasomal activity. KEGG analysis revealed apoptosis suppression, including loss of TRAIL/TNFRSF10 signaling and reduced CASP10, BID, and TP53. This combination of metabolic quiescence and anti-apoptotic protection reflects a survival-optimized phenotype associated with lineage plasticity, therapeutic tolerance, and the aggressive disease trajectories commonly observed in AA prostate cancer. In contrast, Enz-R LNCaP cells exhibited a distinct proliferative resistance state, marked by coordinated upregulation of cell-cycle progression, DNA replication, homologous recombination, mismatch and base-excision repair, p53 signaling, and pyrimidine metabolism. Immune response and adhesion pathways were broadly downregulated, consistent with an immune-evasive, AR-independent phenotype. This proliferative remodeling represents a canonical escape route driven by AR bypass and strengthened genome maintenance pathways. Together, these findings highlight two distinct resistance strategies: a survival-optimized, metabolically repressed, apoptosis resistant program in MDAPCa2b cells and a proliferative, DNA-repair enhanced program in LNCaP cells. These biologically divergent trajectories may contribute to observed clinical disparities and underscore the need for tailored, lineage-informed therapeutic strategies.