Abstract 1722: Targeting synaptotagmin 4 to overcome enzalutamide and abiraterone resistance in castration resistant prostate cancer

Abstract Background: Castration-resistant prostate cancers (CRPCs) are predominantly driven by androgen receptor (AR) signaling. Although next-generation anti-androgen therapies (NGATs), such as enzalutamide (Enza) and abiraterone (Abi), have been shown to extend patient survival, resistance to these therapies often develops. The underlying mechanisms driving resistance to these treatments remains unclear. Synaptogamin 4 (SYT4), a membrane protein involved in vesicle trafficking, is highly expressed in our established Enza and Abi resistant CRPC cells. Here, we explore the contribution of SYT4 in disease progression and NGATs resistance in CRPC. Methods: Differences in SYT4 expression were determined in Enza-resistant C4-2B MDVR (MDVR) and Abi-resistant C4-2B AbiR (AbiR) cells versus parental C4-2B cells by RNA-sequencing, real time PCR, western blot and immunofluorescence microscopy. SYT4 expression was analyzed in GEO and cBioPortal databases from patients with prostate cancer. Specific siRNAs were used to inhibit SYT4 expression. The effect of SYT4 knock down on global gene expression, cell growth and sensitivity to Enza and Abi was assessed in our resistant cell lines. Results: SYT4 gene expression was found to be markedly elevated in MDVR and AbiR cells compared to their parental C4-2B counterparts. Analysis of clinical data further revealed that SYT4 expression is significantly upregulated in patients with advanced prostate cancer; with high SYT4 levels being associated with poorer overall survival outcomes. Transcriptomic profiling identified enrichment of genes involved in calcium-mediated cell adhesion in MDVR cells, which is suppressed upon transfection with SYT4-specific siRNA. Additionally, silencing SYT4 expression via siRNA not only inhibited prostate cancer cell growth but also restored sensitivity of MDVR and AbiR cells to their respective treatments, underscoring SYT4 as a promising therapeutic target for treatment-resistant prostate cancer. Conclusions: Our findings indicate that elevated expression of SYT4 promotes resistance to Enza and Abi; correlating with poorer outcomes in prostate cancer patients. Targeting SYT4 reduces the expression of genes involved in calcium-dependent cell adhesion and reduces cellular viability, thereby restoring sensitivity to NGATs like Enza and Abi, offering potential new strategies for overcoming treatment-resistant prostate cancer. Citation Format: Masuda Sharifi, Shu Ning, Amy Rose Leslie, Zachary A. Schaaf, James Patrick Maine, Wei Lou, Allen C. Gao. Targeting synaptotagmin 4 to overcome enzalutamide and abiraterone resistance in castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1722.