The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance
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Published:2023-12-04
Issue:1
Volume:56
Page:60-73
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Caswell Deborah R.ORCID, Gui Philippe, Mayekar Manasi K., Law Emily K.ORCID, Pich OriolORCID, Bailey Chris, Boumelha JesseORCID, Kerr D. LucasORCID, Blakely Collin M.ORCID, Manabe TadashiORCID, Martinez-Ruiz Carlos, Bakker BjornORCID, De Dios Palomino Villcas Juan, I. Vokes NatalieORCID, Dietzen MichelleORCID, Angelova MihaelaORCID, Gini BeatriceORCID, Tamaki WhitneyORCID, Allegakoen Paul, Wu WeiORCID, Humpton Timothy J.ORCID, Hill William, Tomaschko Mona, Lu Wei-TingORCID, Haderk Franziska, Al Bakir MaiseORCID, Nagano AiORCID, Gimeno-Valiente Francisco, de Carné Trécesson Sophie, Vendramin Roberto, Barbè Vittorio, Mugabo Miriam, Weeden Clare E., Rowan Andrew, McCoach Caroline E., Almeida Bruna, Green Mary, Gomez Carlos, Nanjo ShigekiORCID, Barbosa Dora, Moore Chris, Przewrocka Joanna, Black James R. M.ORCID, Grönroos EvaORCID, Suarez-Bonnet AlejandroORCID, Priestnall Simon L.ORCID, Zverev Caroline, Lighterness Scott, Cormack James, Olivas Victor, Cech LaurenORCID, Andrews Trisha, Rule BrandonORCID, Jiao Yuwei, Zhang Xinzhu, Ashford PaulORCID, Durfee CameronORCID, Venkatesan Subramanian, Temiz Nuri AlpayORCID, Tan Lisa, Larson Lindsay K., Argyris Prokopios P., Brown William L.ORCID, Yu Elizabeth A., Rotow Julia K., Guha UdayanORCID, Roper Nitin, Yu Johnny, Vogel Rachel I.ORCID, Thomas Nicholas J.ORCID, Marra Antonio, Selenica Pier, Yu HelenaORCID, Bakhoum Samuel F., Chew Su Kit, Reis-Filho Jorge S.ORCID, Jamal-Hanjani MariamORCID, Vousden Karen H.ORCID, McGranahan Nicholas, Van Allen Eliezer M.ORCID, Kanu Nnennaya, Harris Reuben S.ORCID, Downward JulianORCID, Bivona Trever G.ORCID, Swanton CharlesORCID
Abstract
AbstractIn 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.
Publisher
Springer Science and Business Media LLC
Reference109 articles.
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