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

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.

SUBMITTER: Caswell DR

PROVIDER: S-EPMC10786726 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Caswell Deborah R DR Gui Philippe P Mayekar Manasi K MK Law Emily K EK Pich Oriol O Bailey Chris C Boumelha Jesse J Kerr D Lucas DL Blakely Collin M CM Manabe Tadashi T Martinez-Ruiz Carlos C Bakker Bjorn B De Dios Palomino Villcas Juan J I Vokes Natalie N Dietzen Michelle M Angelova Mihaela M Gini Beatrice B Tamaki Whitney W Allegakoen Paul P Wu Wei W Humpton Timothy J TJ Hill William W Tomaschko Mona M Lu Wei-Ting WT Haderk Franziska F Al Bakir Maise M Nagano Ai A Gimeno-Valiente Francisco F de Carné Trécesson Sophie S Vendramin Roberto R Barbè Vittorio V Mugabo Miriam M Weeden Clare E CE Rowan Andrew A McCoach Caroline E CE Almeida Bruna B Green Mary M Gomez Carlos C Nanjo Shigeki S Barbosa Dora D Moore Chris C Przewrocka Joanna J Black James R M JRM Grönroos Eva E Suarez-Bonnet Alejandro A Priestnall Simon L SL Zverev Caroline C Lighterness Scott S Cormack James J Olivas Victor V Cech Lauren L Andrews Trisha T Rule Brandon B Jiao Yuwei Y Zhang Xinzhu X Ashford Paul P Durfee Cameron C Venkatesan Subramanian S Temiz Nuri Alpay NA Tan Lisa L Larson Lindsay K LK Argyris Prokopios P PP Brown William L WL Yu Elizabeth A EA Rotow Julia K JK Guha Udayan U Roper Nitin N Yu Johnny J Vogel Rachel I RI Thomas Nicholas J NJ Marra Antonio A Selenica Pier P Yu Helena H Bakhoum Samuel F SF Chew Su Kit SK Reis-Filho Jorge S JS Jamal-Hanjani Mariam M Vousden Karen H KH McGranahan Nicholas N Van Allen Eliezer M EM Kanu Nnennaya N Harris Reuben S RS Downward Julian J Bivona Trever G TG Swanton Charles C

Nature genetics 20231204 1

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 upre ...[more]

PMID: 38049664

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Project description:BackgroundTo investigate the efficacy of a PLGA-based nanobody complex in photodynamic therapy (PDT) and NIR-II imaging in A549 tumor hypoxic model.MethodIR1048-MZ was firstly synthesized by conjugating a nitro imidazole group to IR1048. IR1048-MZ and Cat were then encapsulated in PLGA-SH solution. Anti-EGFR-Nanobody was also expressed and purified, and finally Anti-EGFR-Nanobody@PLGA-IR1048MZ-Cat (Nb@IC-NPs) nanobody complex was obtained based on the formation of desulfide bond between PLGA-SH and Anti-EGFR-Nanobody. Size distribution and morphology were characterized by TEM and DLS. Spectrum of Nb@IC-NPs towards NTR was measured by UV and fluorescence, while the particle's selective response was studied using fluorescence. The uptake of Nb@IC-NPs in A549 cells was observed by flow cytometry and CLSM. In the meantime, its' catalytic ability that decomposes H2O2 both extra-and intra-cellular was observed by fluorescence and CLSM. In vitro photodynamic toxicity of Nb@IC-NPs was examined by MTT, Live/Dead Cell Staining, Flow Cytometry and Apoptosis Assay. Tumor-bearing model was constructed to observe a semi-quantitative fluorescent distribution and the possibility of NIR-II fluorescence/photoacoustic (PA) imaging. Effect of Nb@IC-NPs on enhancing A549 tumor hypoxia and expression profile of HIF-1α was investigated in the presence of NIR. An A549 tumor metastasis model was also constructed to confirm the complex' potential to destroy primary tumor, inhibit lung metastasis, and prolong mice' survival. Lastly, impact of Nb@IC-NPs on mice' main organs and blood indices was observed.ResultsNb@IC-NPs was successfully fabricated with good homogeneity. The fluorescent absorbance of Nb@IC-NPs showed a linear relationship with the concentration of NTR, and a higher concentration of NTR corresponded to a stronger photoacoustic signal. In addition, Nb@IC-NPs showed a stable selectivity toward NTR. Our results also suggested a high efficient uptake of Nb@IC-NPs in A549 cells, which was more efficient than IC-NPs and IR1048-MZ alone. In vitro assays confirmed the effects of Nb@IC-NPs on catalytic O2 generation even in hypoxic cells. The cell viability was upregulated with the nanocomplex at the absence of the laser, whereas it was dramatically declined with laser treatment that excited at 980 nm. Nb@IC-NPs achieved tumor hypoxia NIR-II/PA imaging through assisting A549 gathering. When NIR was applied, Nb@IC-NPs can significantly relieve A549 cellular/tumor hypoxia by generating more reactive oxygen species (ROS), which in turn helps lower the expression level of HIF-1α. In summary, Nb@IC-NPs based PDT can efficiently decimate A549 primary tumor, inhibit metastatic lung cancer, and prolong the lifespan of the mice under tolerable dosage. At last, in vivo toxicity tests of the nanocomplex showed its biosafety to the main organs and normal blood indices values.ConclusionNb@IC-NPs improves tumor hypoxia through catalytic reaction and lowers the expression level of HIF-1α. It achieves tumor PA imaging through intensified NIR-II fluorescence signal that caused by response of the complex to the lesion's nitroreductase (NTR). Nb@IC-NPs based PDT can efficiently kill A549 primary tumor, inhibit a lung metastasis, as well as prolong mice' survival cycle.

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

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

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