The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
Deborah R CaswellPhilippe GuiManasi K MayekarEmily K LawOriol PichChris BaileyJesse BoumelhaD Lucas KerrCollin M BlakelyTadashi ManabeCarlos Martinez-RuizBjorn BakkerJuan De Dios Palomino VillcasNatalie I VokesMichelle DietzenMihaela AngelovaBeatrice GiniWhitney TamakiPaul AllegakoenWei WuTimothy J HumptonWilliam HillMona TomaschkoWei-Ting LuFranziska HaderkMaise Al BakirAi NaganoFrancisco Gimeno-ValienteSophie de Carné TrécessonRoberto VendraminVittorio BarbèMiriam MugaboClare E WeedenAndrew RowanCaroline E McCoachBruna AlmeidaMary GreenCarlos GomezShigeki NanjoDora BarbosaChris MooreJoanna PrzewrockaJames R M BlackEva GrönroosAlejandro Suarez-BonnetSimon Lawrence PriestnallCaroline ZverevScott LighternessJames CormackVictor OlivasLauren CechTrisha AndrewsBrandon RuleYuwei JiaoXinzhu ZhangPaul AshfordCameron DurfeeSubramanian VenkatesanNuri Alpay TemizLisa TanLindsay K LarsonProkopios P ArgyrisWilliam L BrownElizabeth A YuJulia K RotowUdayan GuhaNitin RoperJohnny YuRachel Isaksson VogelNicholas J ThomasAntonio MarraPier SelenicaHelena Alexandra YuSamuel F BakhoumSu Kit ChewJorge Sergio Reis-FilhoMariam Jamal-HanjaniKaren H VousdenNicholas McGranahanEliezer Van AllenNnennaya KanuReuben Stewart HarrisJulian DownwardTrever G BivonaCharles SwantonPublished in: Nature genetics (2023)
In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.
Keyphrases
- cancer therapy
- epidermal growth factor receptor
- small cell lung cancer
- advanced non small cell lung cancer
- nuclear factor
- poor prognosis
- tyrosine kinase
- drug delivery
- brain metastases
- endothelial cells
- toll like receptor
- signaling pathway
- long non coding rna
- crispr cas
- binding protein
- mouse model
- stem cells
- newly diagnosed
- dna methylation
- risk assessment
- mesenchymal stem cells
- single cell
- bone marrow
- immune response
- gene expression
- combination therapy
- lps induced
- diabetic rats
- wild type