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The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.

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posted on 2024-01-18, 11:54 authored by 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 Martinez-Ruiz, Bjorn 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, Ai 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 Gomez, Shigeki Nanjo, Dora Barbosa, Chris Moore, Joanna Przewrocka, James RM Black, Eva Grönroos, Alejandro Suarez-Bonnet, Simon L Priestnall, Caroline Zverev, Scott Lighterness, James Cormack, Victor Olivas, Lauren Cech, Trisha Andrews, Brandon Rule, Yuwei Jiao, Xinzhu Zhang, Paul Ashford, Cameron Durfee, Subramanian 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, 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
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.

Funding

Crick (Grant ID: CC2073, Grant title: Vousden CC2073) Crick (Grant ID: CC2041, Grant title: Swanton CC2041) Crick (Grant ID: CC1061, Grant title: STP Experimental Histopathology) Crick (Grant ID: CC2097, Grant title: Downward CC2097) Crick (Grant ID: CC1109, Grant title: STP BRF) Novo Nordisk UK Research Foundation (Grant ID: NNF15OC0016584, Grant title: NovoNordisk Foundation 16584) European Research Council (Grant ID: 835297 - PROTEUS, Grant title: ERC 835297 - PROTEUS)

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