Abstract 4311: The interplay of SYNCRIP deficiency, APOBEC activity, and extrachromosomal DNA in castration-resistant prostate cancer drug resistance

Abstract

Abstract Background: Prostate cancer, particularly in its castration-resistant form (CRPC), frequently develops resistance to androgen receptor (AR)-targeted therapies. This resistance involves complex factors, including tumor mutational burden and heterogeneity. APOBEC proteins, associated with mutagenesis and DNA damage, are implicated in this process. Our study centers on SYNCRIP, a key regulator of APOBEC activity, and investigates its influence on extrachromosomal DNA (ecDNA) in CRPC. Objective: This research aims to explore how SYNCRIP deficiency leads to increased APOBEC activity, and to examine its possible implications for ecDNA formation and its contribution to drug resistance and tumor heterogeneity in CRPC. Methods: Genomic and transcriptomic analyses, such as whole exome sequencing and single-cell RNA-seq, were performed on CRPC cell lines and patient-derived samples, with an emphasis on SYNCRIP-deficient models. The study focused on understanding the relationship between elevated APOBEC activity due to SYNCRIP deficiency and potential ecDNA changes, evaluating their effect on AR-targeted drug sensitivity and overall tumor behavior. Results: SYNCRIP was identified as a critical factor in resistance to AR therapy in both in vitro and in vivo models. Its deficiency resulted in increased therapy resistance and amplified APOBEC-mediated mutagenesis. Functional CRISPR screening identified eight key drivers of resistance in SYNCRIP-deficient tumors. Single-cell RNA sequencing revealed APOBEC-driven mutagenesis as a key factor in promoting intratumoral heterogeneity and resistance. Notably, in SYNCRIP-deficient CRPC samples, increased APOBEC activity and significant DNA damage were observed, prompting an investigation into a possible correlation between resistance and ecDNA presence. Conclusion: The study uncovers a significant link between SYNCRIP deficiency and increased APOBEC activity in CRPC. While it also hints at a potential connection with ecDNA alterations, further research is necessary to establish this relationship firmly. This interplay contributes to the complexity of drug resistance in CRPC, highlighting the need for novel therapeutic targets. The dynamics among SYNCRIP, APOBEC activity, and ecDNA offer valuable insights into the molecular underpinnings of therapy resistance in prostate cancer, suggesting new directions for treatment strategies. Citation Format: Xiaoling Li, Su Deng, Choushi Wang, Yunguan Wang, Ping Mu. The interplay of SYNCRIP deficiency, APOBEC activity, and extrachromosomal DNA in castration-resistant prostate cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4311.