Abstract 483: Organoids-based high-throughput drug screening identifies selective vulnerability of AR-/lo CRPC to inhibitors of neurotransmission signaling.

Abstract Introduction of the next generation of potent antiandrogens (abiraterone, enzalutamide, apalutamide, darolutamide) about a decade ago into the clinical management of advanced prostate cancer (PCa) patients has led to a substantial increase in a subtype of castration-resistant PCa (CRPC) that becomes independent of androgen receptor (AR) signaling and frequently lacks AR expression (i.e., AR-/lo). The AR-/lo CRPC is de novo resistant to castration and enzalutamide (Enza), and there are currently no targeted therapies available for this subtype. To identify novel regulators and therapeutic targets in AR-/lo CRPC, we developed an organoids platform from the AR-/lo LAPC9-AI (androgen-independent, i.e., CRPC) xenograft model (Li and Deng et al., Nat. Commun. 2018) that recapitulates the AR-/lo CRPC phenotype and drug responsiveness. Using this platform, we conducted high-throughput screening (HTS) in a total of ∼6,000 compounds and drugs (including 4,480 bioactive agents and 1,508 FDA-approved drugs). Secondary screening and validation experiments, surprisingly, uncovered 21 compounds effective in inhibiting the AR-/lo CRPC organoids, including JTC-801, Penfluridol and Terfenadine, which normally target the G protein-coupled receptors activated by neurotransmitters including dopamine receptor and opioid receptor. Notably, JTC-801 and Penfluridol specifically inhibited the growth of AR-/lo LAPC9-AI in vivo. Collectively, our study identifies novel therapeutic vulnerabilities in castration/Enza-resistant AR-/lo CRPC. Citation Format: Shan Wu, Ruize Zhao, Xiaozhuo Liu, Wen (Jess) Li, Moyi Wang, Amanda Tracz, Henry Withers, Brian Buckley, Katerina Gurova, Prashant Singh, Eduardo Cortes, Jianmin Wang, Jason S. Kirk, Dean G. Tang. Organoids-based high-throughput drug screening identifies selective vulnerability of AR-/lo CRPC to inhibitors of neurotransmission signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 483.