Base editing encompasses techniques that efficiently alter specific nucleotides at the DNA or RNA level. Initially explored for inherited diseases, these techniques hold promise for addressing various genetically driven disorders caused by single nucleotide variants (SNVs). The precise programmability of base editors (BEs) for specific sequences allows customization for rare genetic variants, tailoring them to individual patients within affordability and delivery constraints.

Cancer stems from the accumulation of mutations. However, the relevance of BEs in cancer therapy is doubted due to the limited types of mutations they can address within tumors. Yet, their untapped potential in the realm of cancer treatment invites exploration.

BEs utilize a modified form of a deaminase enzyme to catalyze the conversion of one nucleotide to another by removing an amino group. A 'classic' BE consists of a deaminase, a Cas nuclease, and a guide RNA (gRNA) ensuring target specificity through Watson-Crick base pairing. An alternative RNA BE, known as Endogenous-ADAR, involves designing a gRNA to recruit native Adenosine Deaminases Acting on RNA (ADAR), responsible for extensive A-to-I(G) editing in mammals. Due to its reliance on ADAR capabilities, Endogenous-ADAR exclusively targets G>A SNVs at the RNA level. Notably, RNA editing, occurring before splicing, provides the flexibility to target all gene regions. Also, editing the RNA sequence is considered 'safer' in the event of an off-target error.

Our objective is to systematically explore the potential of Endogenous-ADAR for cancer prevention and treatment. Our first approach evaluates Endogenous-ADAR's potential to revert germline mutations in cancer predisposition genes (CPGs) for cancer prevention. Focusing on CPGs recommended for pediatric genetic testing by NCBI, associated with cancer predisposition disorders, our findings indicate that among the 2,820 SNVs examined, 566 (20%) are suitable for Endogenous-ADAR. Remarkably, 88% of correctable variants show no off-target sites, indicating safe therapeutic targets. Further examining pathogenic high-penetrance germline variants in adults, 48 (20%) of the 239 SNVs examined are correctable using Endogenous-ADAR.

Second, we estimate the potential to correct cancer driver mutations. Examining 5,913 driver mutations from 2,010 patients representing 36 cancer types, which underwent whole genome sequencing (WGS) in the PCWAG project, we find that 955 (16%) are suitable for Endogenous-ADAR. In 729 (36%) of patients, at least one driver mutation is correctable, and in 91 (5%), all known driver mutations are correctable.

Aligned with the swift incorporation of WGS in oncology, our systematic exploration portrays a favorable landscape of correctable mutations in cancer. This points to the future possibility of leveraging the unique capabilities of base editing, particularly Endogenous-ADAR, for clinical cancer risk/prevention and treatment outcomes.

Citation Format: Rona Merdler-Rabinowicz, Ariel Dadush, Sumeet Patiyal, Padma Sheila Rajagopal, Gulzar Daya, Alejandro Schäffer, Eli Eisenberg, Eytan Ruppin, Erez Y. Levanon. A systematic evaluation of the therapeutic potential of Endogenous-ADAR base editors in cancer prevention and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB007.