Abstract Small-cell neuroendocrine prostate carcinoma (SC/NEPC) is an aggressive subtype of prostate cancer (PC) with poor response to conventional therapies and no approved targeted therapies. The molecular mechanisms that drive the growth and survival of these tumors are poorly understood due to disease rarity and a lack of model systems for the subtype. SC/NEPC shares defining characteristics with other aggressive small-cell neuroendocrine tumors, such as “small-blue round cell” morphology and expression of chromogranin A. In this study, we compare whole transcriptome RNA-sequencing data from metastatic PCs and two additional SC/NE tumor types, small cell lung cancer (SCLC) and Merkel Cell carcinoma (MCC). By differential expression analysis of each neuroendocrine tumor type to Androgen Receptor-responsive Prostate Cancer (AR-PC), we identify 4,300 genes exhibiting shared expression patterns in multiple neuroendocrine tumor types. Among these “pan-neuroendocrine” genes are known and proposed drivers of the neuroendocrine transcriptional program including MYCN (p=8.7E-07, upregulated in SC/NEPC over AR-PC) and potential novel drivers of the neuroendocrine phenotype in PC such as MYCL (p=3.5E-05, upregulated in SC/NEPC over AR-PC). We also identify conserved expression patterns of druggable targets including BCL2 which has previously been reported as highly expressed in subsets of SCLC and MCC, but not SC/NEPC (p=1.24E-05, upregulated in SC/NEPC over AR-PC). We then analyzed a panel of cell lines and novel PDX models, which further confirm that the BCL2 protein is highly expressed specifically in the SC/NEPC phenotype. We determined that SC/NEPC cell lines and PDX models are sensitive to BCL2 family member inhibitors targeting BCL2, BCLXL, BCLW, including, ABT263, ABT199 and ABT737, at sub-micromolar concentrations, whereas models of ARPC were resistant. These inhibitors lead to apoptotic cell death in SC/NEPC. Collectively, our data suggests that BCL2 inhibition may present a novel targeted approach for SC/NEPC that warrants further evaluation. Citation Format: Alexandra N. Corella, Jared M. Lucas, Arja Kaipainen, Ilsa M. Coleman, Colm Morrissey, Eva Corey, Paul Nghiem, David MacPherson, Peter S. Nelson. Targeting BCL2 as a therapeutic strategy in neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2962.