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The APOBEC cytidine deaminase enzyme family is linked to mutational signatures identified in cancer. While previous work has provided insights into the role of APOBEC3A and APOBEC3B in mutational processes in cancer, understanding of the mutational signatures induced by other APOBEC family members is limited. In this issue of Cancer Research, Liu and colleagues investigated the role of APOBEC3G (A3G) in bladder cancer. The authors revealed that transgenic expression of A3G in a murine bladder cancer model promotes tumorigenesis and induces a unique mutational signature distinct from previously identified APOBEC signatures. Expression of this A3G-related mutational signature correlated with significantly worse survival in patients with urothelial bladder carcinoma, and A3G expression was identified in 21 different cancer types. These findings suggest that different APOBEC3 enzymes induce unique mutation signatures and play distinct roles in cancer evolution. More complete understanding of the function of each APOBEC3 enzyme will improve anticancer therapy.See related article by Liu et al., p. 506

Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2197.