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EGFR inhibition rapidly induces APOBEC3 expression and activity, promoting drug-tolerant persister cell survival and altering resistance evolution to gefitinib. APOBEC3B increases ΔNp63 expression, links to squamous transdifferentiation, and p63 loss reduces target genes and sensitizes cells to osimertinib.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/apobec3-activity-promotes-the-survival-and-evolution-of-drug-tolerant-persister-cells-during-egfr-inhibitor-resistance-in-lung-cancer/371491/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/apobec3-activity-promotes-the-survival-and-evolution-of-drug-tolerant-persister-cells-during-egfr-inhibitor-resistance-in-lung-cancer/371491.png","ImageObject",300,407,{"name":42,"@type":43},"Sophia 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ACCESS  \nAPOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer  \nNina Marie G. Garcia1,2, Jessica N. Becerra1, Sharan Srinivasan1, Brock J. McKinney1, Ashley V. DiMarco2, Feinan Wu3, Matthew Fitzgibbon3, and James V. Alvarez1  \n􀀶  \nABSTRACT  \nAPOBEC 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 mutagenesisto 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 EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises through de novo acquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of  \nthe squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinibresistant cells reduces the expression of the ΔNp63 target genes IL-1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs and that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.  \nSignificance: APOBEC mutagenesis is a common source of genetic heterogeneity in cancer, and APOBEC mutational signatures are enriched in metastatic and drug-resistant tumors. However, the mechanisms through which APOBEC3 enzymes promote tumor evolution remain unknown. In this study, we show that APOBEC3 activity contributes to the development of therapy-resistant cancer cells by promoting evolution of DTP cells. These findings offer insights into the role of APOBEC mutagenesis in cancer progression.  \nIntroduction  \nThe APOBEC mutational signature, characterized by C-to-T transitions and C-to-G transversions occurring in a TpCpW context, is a prominent mutational process in multiple tumor types, including lung adenocarcinomas ( 1–5). APOBEC mutagenesis results from the activity of the APOBEC3A and APOBEC3B enzymes, which deaminate cytosines on single-stranded DNA (6–9). APOBEC mutagenesis and expression of APOBEC3A and APOBEC3B genes are associated with poor prognosis and intratumor heterogeneity and are  \n1Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington. 2Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. 3Genomicsand Bioinformatics, Fred Hutchinson Cancer Center, Seattle, Washington.  \nCorresponding Author: James V. Alvarez, Fred Hutchinson Cancer Center,  \n1100 Fairview Avenue N, M5-C803, Seattle, WA 98109. E-mail: [jalvarez@fredhutch.org](jalvarez@fredhutch.org)  \n[doi:](doi: 10.1158/2767-9764)[ 10.1158/2767-9764](doi: 10.1158/2767-9764) .CRC-24-0442  \nThis open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.  \n©2025 The Authors; Published by the American Association for Cancer Research  \nincreased in metastatic and drug-resistant tumors ( 10–14).","cbCaintN3XRXXH8z","https://ap.wps.com/l/cbCaintN3XRXXH8z","pdf",8101368,16,"English","# Abstract\n# Significance\n# Introduction\n# Materials and Methods\n# Results\n# Discussion","[{\"question\":\"What happens to APOBEC3 expression when EGFR is inhibited in lung cancer cells?\",\"answer\":\"EGFR inhibition triggers a rapid and pronounced induction of APOBEC3 expression and APOBEC3 activity.\"},{\"question\":\"How does APOBEC activity influence therapy resistance in the study model?\",\"answer\":\"APOBEC expression promotes survival of drug-tolerant persister cells and shifts acquired resistance evolution to gefitinib toward de novo T790M acquisition and squamous transdifferentiation.\"},{\"question\":\"What is the effect of knocking out p63 in gefitinib-resistant cells?\",\"answer\":\"p63 knockout reduces ΔNp63 target gene expression (IL-1α/β) and sensitizes resistant cells to the third-generation EGFR inhibitor osimertinib.\"}]","APOBEC3 Activity Promotes the Survival and Evolution of Drug-Tolerant Persister Cells during EGFR Inhibitor Resistance in Lung Cancer | PDF",1790192199]