Molecular decoupling of lineage identity and morphology in aggressive variant prostate cancer.

Aggressive variant prostate cancer (AVPC) is a lethal subtype of prostate cancer characterized by its androgen independence, resistance to chemotherapy, and display of neuroendocrine features which can emerge either de novo or via transformation after a prior diagnosis of adenocarcinoma. The poor clinical outcomes in patients with AVPC are associated with its profound molecular heterogeneity. In this study, we analyzed 23 consecutive AVPC cases treated at a dedicated small-cell clinic (2017-2025) using clinicogenomic and transcriptomic profiling. Transformed AVPC exhibited significantly shorter overall survival times than de novo AVPC (11.8 vs 26.0 months, P < 0.001). Integrative genomic analyses identified residual androgen signaling in subsets of cases harboring neuroendocrine lineage programs, highlighting a decoupling of lineage identity and morphology. To facilitate mechanistic and pharmacologic studies, we established NCI-LYM-1, a patient-derived organoid/PDX from an AR-negative, ASCL1+/SYP+ lymph node metastasis, which faithfully recapitulates the donor tumor's molecular and phenotypic features. Short- and long-read whole-genome sequencing combined with optical genome mapping identified biallelic inactivation of PTEN, TP53, RB1 and BRCA2 as potential drivers, demonstrating clonal concordance with circulating tumor DNA from the original patient donor. Pathway and perturbation analyses suggested that NCI-LYM-1 harbored a strong dependency on apoptotic pathways, which was confirmed by in vitro organoid testing with the BCL-2/BCL-xL inhibitor navitoclax (IC50: 0.27 μM) and the MCL-1 inhibitor AZD-5991 (IC50: 0.060 μM). Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.