Functional and molecular characterization of the first large cell neuroendocrine prostate cancer cell line

Background Prostate cancer is the fourth most common cancer worldwide. Despite the high incidence rate, in vitro research of prostate cancer has been limited to fewer than ten commonly available cell lines. The limited availability of disease-representative model cell lines is a widely acknowledged challenge in translational prostate cancer research. Establishment of novel prostate cancer cell lines is therefore of critical importance to facilitate functional target discovery and drug development for prostate cancer. Methods In this study, we report the establishment of the first large cell neuroendocrine prostate cancer cell line, MISB114, from a liver metastasis of an aggressive castration resistant neuroendocrine prostate cancer. Comparative transcriptomic, DNA sequencing and high-throughput drug screening against the currently available prostate cancer cell lines and molecular profiling of prostate cancers are used for characterization of the MISB114 cell line. Results MISB114 cells are characterized by aggressive large cell neuroendocrine prostate cancer associated molecular features including high neuronatin and somatostatin expression, androgen independency and complete inactivation of TP53 and RB1. High-throughput drug screening studies indicate a drug sensitivity profile reflecting the dual TP53/RB1 loss associated with elevated replication stress and sensitivity to DNA repair targeting and novel therapeutic targets such as RNA N 6 -methyladenosine regulator METTL3. Conclusion Large cell neuroendocrine prostate cancer is a rare entity of castration resistant prostate cancer. Due to a lack of validated markers for diagnosis, large cell neuroendocrine prostate cancer is generally under-recognized, and the therapeutic implications remain poorly understood. While stable patient derived cell lines best represent the individual tumor of origin, MISB114 cell line provides an invaluable novel model for the study of pathogenesis, molecular characteristics and drug sensitivity of this aggressive neuroendocrine differentiated prostate cancer subtype. Data is available through EMBL-EBI European Nucleotide Archive under accession no. ERP181257. This study has not received any external funding.