The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
Creators: name: Caswell, Deborah R
name: Gui, Philippe
name: Mayekar, Manasi K
name: Law, Emily K
name: Pich, Oriol
name: Bailey, Chris
name: Boumelha, Jesse
name: Kerr, D Lucas
name: Blakely, Collin M
name: Manabe, Tadashi
name: Martinez-Ruiz, Carlos
name: Bakker, Bjorn
name: De Dios Palomino Villcas, Juan
name: Vokes, Natalie I
name: Dietzen, Michelle
name: Angelova, Mihaela
name: Gini, Beatrice
name: Tamaki, Whitney
name: Allegakoen, Paul
name: Wu, Wei
name: Humpton, Timothy J
name: Hill, William
name: Tomaschko, Mona
name: Lu, Wei-Ting
name: Haderk, Franziska
name: Al Bakir, Maise
name: Nagano, Ai
name: Gimeno-Valiente, Francisco
name: de Carné Trécesson, Sophie
name: Vendramin, Roberto
name: Barbè, Vittorio
name: Mugabo, Miriam
name: Weeden, Clare E
name: Rowan, Andrew
name: McCoach, Caroline E
name: Almeida, Bruna
name: Green, Mary
name: Gomez, Carlos
name: Nanjo, Shigeki
name: Barbosa, Dora
name: Moore, Chris
name: Przewrocka, Joanna
name: Black, James RM
name: Grönroos, Eva
name: Suarez-Bonnet, Alejandro
name: Priestnall, Simon L
name: Zverev, Caroline
name: Lighterness, Scott
name: Cormack, James
name: Olivas, Victor
name: Cech, Lauren
name: Andrews, Trisha
name: Rule, Brandon
name: Jiao, Yuwei
name: Zhang, Xinzhu
name: Ashford, Paul
name: Durfee, Cameron
name: Venkatesan, Subramanian
name: Temiz, Nuri Alpay
name: Tan, Lisa
name: Larson, Lindsay K
name: Argyris, Prokopios P
name: Brown, William L
name: Yu, Elizabeth A
name: Rotow, Julia K
name: Guha, Udayan
name: Roper, Nitin
name: Yu, Johnny
name: Vogel, Rachel I
name: Thomas, Nicholas J
name: Marra, Antonio
name: Selenica, Pier
name: Yu, Helena
name: Bakhoum, Samuel F
name: Chew, Su Kit
name: Reis-Filho, Jorge S
name: Jamal-Hanjani, Mariam
name: Vousden, Karen H
name: McGranahan, Nicholas
name: Van Allen, Eliezer M
name: Kanu, Nnennaya
name: Harris, Reuben S
name: Downward, Julian
name: Bivona, Trever G
name: Swanton, Charles
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Model organisms
subject: Model organisms

description: 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.