LAUSR

Neuroendocrine prostate cancer (NEPC) is a lethal variant of aggressive prostate cancer. Hallmarks of NEPC include the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which result in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and genomically. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency with RET kinase, an emerging therapeutic target of NEPC, suggesting the NEPC-like phenotype of the cells. Then, we observed a strong correlation between dependencies of RET and ZBTB7A in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we revealed distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression in NEPC, and this result was confirmed through Gene Set Enrichment Analysis. Furthermore, we showed a potential interaction of ZBTB7A with apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency of cells on ZBTB7A for cell growth, and the role of ZBTB7A in regulating G1/S transition in cell cycle and inducing apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC, and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors. Citation Format: Song Yi Bae, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, Justin M. Drake. ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B057.