biostudies-literatureGarcia NMGNCI NIH HHS825-840https://www.ebi.ac.uk/biostudies/studies/S-EPMC12093302biostudies-literatureUnknown5(5)APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTP) following EGFRCancer research communicationsAPOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer.PMC12093302P30 CA015704R01 CA285322R01 CA208042Alvarez JVMcKinney BJGarcia NMGFitzgibbon MSrinivasan SDiMarco AVBecerra JNWu FfalseAPOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer.APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTP) following EGFR2025-01-01T00:00:00Z2025 May2026-06-01T10:23:55.383Z2026-04-08T11:26:28.929ZS-EPMC120933024032301310.1158/2767-9764.CRC-24-0442