Enzalutamide-induced signatures revealed by epigenetic plasticity using single-cell multi-omics sequencing in prostate cancer

Prostate cancer is morphologically and molecularly heteroge-neous, which poses obstacles for early diagnosis and treatment. Advancements in understanding the heterogeneity of prostate cancer will help navigate through these challenges and ulti-mately benefit patients. In this study, we integrated single -cell sequencing for transposase-accessible chromatin and whole transcriptome in prostate cancer cell lines, aiming to decode the epigenetic plasticity upon enzalutamide (ENZ) treatment. By comparing the cell populations representing early-treat-ment response or resistance to the initial tumor cells, we iden-tified seven signature gene sets; they present consistent trends of chromatin closing co-occurred with down-regulated genes during early response and chromatin opening with up-regu-lated genes upon maintaining drug resistance. In the molecular signatures, we found genes ZNF337, MAPK15, and ESRRG are favorable in progression-free prognosis during early response, while genes CCDC150, CCDC18, and POC1A marked poor prognosis underpinning the pre-existing drug resistance in The Cancer Genome Atlas prostate adenocarcinoma cohort. Ultimately, drug-target analyses nominated combinatory drug candidates to either enhance early-treatment response or potentially overcome ENZ resistance. Together, our integra-tive, single-cell multi-omics approach in pre-clinical models is effective in identifying informative signatures from complex molecular events, illustrating diverse drug responses in pros-tate cancer, and invoking novel combinatory drug strategies to inform clinical decision making.