Abstract 7460: Unveiling NEPC vulnerabilities through single-cell analysis and drug screening

Abstract Neuroendocrine prostate cancer (NEPC) represents an aggressive, treatment-resistant disease that emerges following androgen deprivation therapy. Despite growing evidence supporting transdifferentiation from luminal cells, the cellular origins and developmental trajectories remain poorly understood. Through comprehensive integration of single-cell RNA sequencing data from 318 human prostate cancer samples and 179 mouse models, analyzing over one million cells, we identified distinct neuroendocrine subpopulations as well as both convergence and diversity among non-neoplastic cells (especially fibroblasts and immune cells). These ongoing efforts are expected to provide an unprecedented comprehensive view of prostate cancer heterogeneity and unravel critical cellular and molecular differences between treatment-induced and de novo NEPC. Using our established dual-luciferase reporter system in NEPC cells, we screened 290 compounds and identified 19 AR-inducing compounds and 44 NEPC-selective compounds. Among these, several promising candidates showed significant therapeutic windows, including compounds targeting inflammatory pathways and epigenetic regulators, with one compound demonstrating 100-fold selectivity for NEPC cells compared to AR-positive prostate cancer cells. Additionally, we found that while NEPC cells retain basic AR signaling machinery, AR expression alone was insufficient to restore sensitivity to AR pathway inhibitors, highlighting the complexity of targeting cellular plasticity in NEPC. This integrative approach combining computational analysis with experimental validation provides new insights into NEPC development and presents novel therapeutic opportunities for this aggressive disease. Our ongoing work aims to validate these findings through cross-species comparative analyses and detailed mechanistic studies. Citation Format: Ziyu Zeng, Yan Liu, Aktar Ali, Xin Lu. Unveiling NEPC vulnerabilities through single-cell analysis and drug screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7460.