학술논문
The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance
Document Type
article
Author
Caswell, Deborah R; Gui, Philippe; Mayekar, Manasi K; Law, Emily K; Pich, Oriol; Bailey, Chris; Boumelha, Jesse; Kerr, D Lucas; Blakely, Collin M; Manabe, Tadashi; Martinez-Ruiz, Carlos; Bakker, Bjorn; De Dios Palomino Villcas, Juan; I. Vokes, Natalie; Dietzen, Michelle; Angelova, Mihaela; Gini, Beatrice; Tamaki, Whitney; Allegakoen, Paul; Wu, Wei; Humpton, Timothy J; Hill, William; Tomaschko, Mona; Lu, Wei-Ting; Haderk, Franziska; Al Bakir, Maise; Nagano, Ai; 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, Shigeki; Barbosa, Dora; Moore, Chris; Przewrocka, Joanna; Black, James RM; Grönroos, Eva; Suarez-Bonnet, Alejandro; Priestnall, Simon L; Zverev, Caroline; Lighterness, Scott; Cormack, James; Olivas, Victor; Cech, Lauren; Andrews, Trisha; Rule, Brandon; Jiao, Yuwei; Zhang, Xinzhu; Ashford, Paul; Durfee, Cameron; Venkatesan, Subramanian; Temiz, Nuri Alpay; Tan, Lisa; Larson, Lindsay K; Argyris, Prokopios P; Brown, William L; Yu, Elizabeth A; Rotow, Julia K; Guha, Udayan; Roper, Nitin; Yu, Johnny; Vogel, Rachel I; Thomas, Nicholas J; Marra, Antonio; Selenica, Pier; Yu, Helena; Bakhoum, Samuel F; Chew, Su Kit; Reis-Filho, Jorge S; Jamal-Hanjani, Mariam; Vousden, Karen H; McGranahan, Nicholas; Van Allen, Eliezer M; Kanu, Nnennaya; Harris, Reuben S; Downward, Julian; Bivona, Trever G; Swanton, Charles
Source
Nature Genetics. 56(1)
Subject
Language
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.