Abstract 137: Epigenetic regulation of APOBEC3A mutagenesis and tumor evolution during targeted therapy in non-small cell lung cancer

Abstract Acquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. We recently demonstrated that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug tolerant cancer cells persisting during therapy. Preventing therapy-induced A3A mutagenesis by gene deletion decreased the accumulation of chromosomal aberrations and delayed the emergence of drug resistance. Thus, we hypothesize that inhibition of A3A may represent a potential therapeutic strategy to halt the evolution of resistant clones and prevent acquired resistance to lung cancer targeted therapies. Understanding the molecular mechanism of A3A induction during targeted therapy is a crucial step to develop targeting A3A therapies.Using a targeted drug combination screen, we found that DNA methyltransferase (DNMT) inhibitors induce expression of APOBEC3A in non-small cell lung cancer cells, phenocopying the effects of targeted therapies. RNA-seq profiling revealed that both targeted therapies and DNMT inhibitors increase expression of non-coding repeat RNAs. Repeatome analysis identified distinct classes of non-codding RNAs including endogenous retrovirus elements (ERV) in drug tolerant persister cells. Activation of endogenous intracellular viral sensing pathways by exogenous nucleic acids mimicking viral infection induced APOBEC3A, and genetic perturbation of RIG-I or MAVS reduced APOBEC3A induced by targeted therapy. These findings suggest that epigenetic derepression of retroviral repeat elements may underly APOBEC3A mutagenic activity and tumor evolution during lung cancer targeted therapy. Citation Format: Hideko Isozaki, Ramin Sakhtemani, Naveed Nikpour, Susanna Monroe, Jessica Lin, Lecia Sequist, Zofia Piotrowska, Justin Gainor, Rémi Buisson, Michael Lawrence, Aaron Hata. Epigenetic regulation of APOBEC3A mutagenesis and tumor evolution during targeted therapy in non-small cell lung cancer [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 137.