The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance
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Deborah Caswell Philippe Gui Manasi K Mayekar Emily K Law Oriol Pich Chris Bailey Jesse Boumelha D Lucas Kerr Collin M Blakely Tadashi Manabe Carlos Martinez-Ruiz Bjorn Bakker Juan De Dios Palomino Villcas Natalie I Vokes Michelle Dietzen Mihaela Angelova Beatrice Gini Whitney Tamaki Paul Allegakoen Wei Wu Tim Humpton William Hill Mona Tomaschko Wei-Ting Lu Franziska Haderk Maise Al Bakir Ai Nagano Francisco Gimeno-Valiente Sophie de Carne Roberto Vendramin Vittorio Barbè Miriam Mugabo Clare Weeden Andrew Rowan Caroline E McCoach Bruna Almeida Mary Green Carlos Gomez Shigeki Nanjo Dora Barbosa Christopher Moore Aska (Joanna) Przewrocka James RM Black Eva Gronroos Alejandro Suarez-Bonnet Simon Priestnall Caroline Zverev Scott Lighterness James Cormack Victor Olivas Lauren Cech Trisha Andrews Brandon Rule Yuwei Jiao Xinzhu Zhang Paul Ashford Cameron Durfee Mani Venkatesan Nuri Alpay Temiz Lisa Tan Lindsay K Larson Prokopios P Argyris William L Brown Elizabeth A Yu Julia K Rotow Udayan Guha Nitin Roper Johnny Yu Rachel I Vogel Nicholas J Thomas Antonio Marra Pier Selenica Helena Yu Samuel F Bakhoum SuKit Chew Jorge S Reis-Filho Mariam Jamal-Hanjani Karen Vousden Nicholas McGranahan Eliezer M Van Allen Nnennaya Kanu Reuben S Harris Julian Downward Trever G Bivona Charles Swanton
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Abstract
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.
Journal details
Journal
Nature Genetics
Volume
56
Issue number
1
Pages
60-73
Available online
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10.1038/s41588-023-01592-8
Europe PubMed Central
38049664
Pubmed
38049664
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