Integrative molecular analyses of lineage identity and morphology in aggressive variant prostate cancer.

Aggressive variant prostate cancer (AVPC) is a lethal subtype of prostate cancer characterized by androgen independence, resistance to chemotherapy, and neuroendocrine features that can emerge 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 AVPC cases using clinicogenomic and transcriptomic profiling. Transformed AVPC exhibited shorter overall survival than de novo AVPC (11.8 vs. 26.0 months). Integrative analyses identified regulators of neuronal processes in subsets of cases with neuroendocrine lineage programs, delineating a spectrum of lineage identity and morphology. To facilitate mechanistic and pharmacologic studies, we established NCI-LYM-1, a patient-derived organoid/PDX from a lymph node metastasis that faithfully recapitulates the donor tumor's molecular and phenotypic features. Genomic profiling identified biallelic inactivation of PTEN, TP53, RB1, and BRCA2 as potential drivers. These alterations were clonally concordant with circulating tumor DNA from the 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 BCL-2/BCL-xL and MCL-1 inhibitors. Overall, NCI-LYM-1 recapitulates the clinical aggressiveness and heterogeneity of AVPC, providing a tractable platform to identify novel precision therapies.