Abstract 93: An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance

Abstract Tumor mutational burden and heterogeneity fuel resistance to many targeted therapies, which inevitably limits the clinical outcome of patients. The cytosine deaminase APOBEC proteins are major drivers of mutagenesis in human cancer, with over 70% of tumors exhibiting a mutational signature that is impacted by APOBEC activity. Nevertheless, the mechanisms through which tumor cells hijack the powerful APOBEC mutagenesis machinery to promote heterogeneity and therapy resistance remain largely unknown. Through a multi-disciplinary approach integrating bulk and single cell RNA-Seq (scRNA-Seq), whole-genome exome-sequencing (WES), and CRISPR library screening, we identified a long sought-after cell-intrinsic mechanism that prevents APOBEC-driven mutagenesis in non-malignant cells. The loss of this “molecular brake”, unleashes APOBEC3B-driven mutagenesis in malignant cells, which then becomes a key mutator and represents the long sought-after molecular source of driver mutations in some frequently mutated genes in cancers, including FOXA1, EP300, and AR. Functional screening identified eight crucial drivers for Androgen Receptor (AR)-targeted therapy resistance in prostate cancer that are mutated by APOBEC3B: BRD7, CBX8, EP300, FOXA1, HDAC5, HSF4, STAT3 and AR. Finally, contrary to conventional understanding, our study reveals that driver mutations in FOXA1 induced by APOBEC3B, not mutations in AR, evolutionarily outcompete other driver mutations and eventually dominate the resistant tumors. Collectively, these results uncover a cell-intrinsic mechanism that unleashes APOBEC-driven mutagenesis, which plays a significant role in conferring targeted therapy resistance and could be the potential therapeutic targets to overcome resistance. Citation Format: Ping Mu, Xiaoling Li, Yunguan Wang, Tao Wang, Su Deng. An endogenous molecular brake preventing APOBEC-driven tumor mutational burden, heterogeneity and therapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 93.