The role of APOBEC3B in lung tumor evolution and targeted cancer therapy resistance.
Caswell DR., Gui P., Mayekar MK., Law EK., Pich O., Bailey C., Boumelha J., Kerr DL., Blakely CM., Manabe T., Martinez-Ruiz C., Bakker B., De Dios Palomino Villcas J., I Vokes N., Dietzen M., Angelova M., Gini B., Tamaki W., Allegakoen P., Wu W., Humpton TJ., Hill W., Tomaschko M., Lu W-T., Haderk F., Al Bakir M., Nagano A., Gimeno-Valiente F., de Carné Trécesson S., Vendramin R., Barbè V., Mugabo M., Weeden CE., Rowan A., McCoach CE., Almeida B., Green M., Gomez C., Nanjo S., Barbosa D., Moore C., Przewrocka J., Black JRM., Grönroos E., Suarez-Bonnet A., Priestnall SL., Zverev C., Lighterness S., Cormack J., Olivas V., Cech L., Andrews T., Rule B., Jiao Y., Zhang X., Ashford P., Durfee C., Venkatesan S., Temiz NA., Tan L., Larson LK., Argyris PP., Brown WL., Yu EA., Rotow JK., Guha U., Roper N., Yu J., Vogel RI., Thomas NJ., Marra A., Selenica P., Yu H., Bakhoum SF., Chew SK., Reis-Filho JS., Jamal-Hanjani M., Vousden KH., McGranahan N., Van Allen EM., Kanu N., Harris RS., Downward J., Bivona TG., Swanton C.
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.