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