Abstract 2938: APOBEC3B and TKI resistance in EGFR mutant lung cancer

Lung cancer is the leading cause of cancer-related deaths worldwide. EGFR mutations, which account for about 25% of lung cancer cases, are more commonly associated with lung cancer in never smokers. Although response rates to EGFR tyrosine kinase inhibitors (TKI) used as a first line therapy are high, acquired resistance inevitably occurs. Elevated tumor mutation burden in EGFR mutant lung cancer is associated with a shorter progression free survival, and worse overall survival with both first and second generation TKIs. Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. APOBEC-driven mutagenesis has been shown to occur in multiple cancer types including lung adenocarcinoma. Using the TCGA and TRACERx datasets we have demonstrated that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR mutant lung adenocarcinoma, and that the APOBEC mutation signature is enriched in a subset of patients with EGFR mutant lung adenocarcinoma. To model APOBEC mutagenesis in lung cancer, we have developed a novel lung cancer mouse model, by crossing the ROSA26LSL-APOBEC3B (A3B) mouse model with several different EGFR mutant mouse models. Using these models, we find that APOBEC3B expression is selected for post-TKI and contributes to resistance to TKI therapy. Citation Format: Deborah Caswell, Manasi Mayekar, Emily Law, William Hill, Eva Gronroos, Reuben Harris, Trever Bivona, Charles Swanton. APOBEC3B and TKI resistance in EGFR mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2938.