美国加州大学旧金山分校Trever G. Bivona等研究人员合作揭示APOBEC3B在肺部肿瘤演变和癌症靶向治疗耐药性中的作用。相关论文于2023年12月4日在线发表在《自然—遗传学》杂志上。

研究人员评估了脂蛋白B mRNA编辑催化亚基样（APOBEC）酶APOBEC3B（A3B）对表皮生长因子受体（EGFR）驱动的肺癌的影响。A3B在表皮生长因子受体突变（EGFRmut）非小细胞肺癌（NSCLC）小鼠模型中的表达限制了肿瘤的发生，而A3B在接受EGFR靶向癌症治疗的肿瘤中的表达则与治疗耐药性有关。对接受EGFR靶向治疗的人类NSCLC模型进行的分析表明A3B上调，并发现治疗诱导的核因子kappa B（NF-κB）激活是A3B表达的诱导因子。

在靶向疗法治疗的人类NSCLC临床前模型中，研究人员观察到A3B缺乏会显著降低生存能力，A3B是APOBEC突变特征富集的必要条件。在接受EGFR靶向治疗的NSCLC患者中，A3B的上调得到了证实。这项研究揭示了A3B在NSCLC中的多方面作用，并确定A3B是使癌症靶向治疗产生更持久反应的潜在靶点。

附：英文原文

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

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 Carn Trcesson, Sophie, Vendramin, Roberto, Barb, 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 R. M., Grnroos, 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

Issue&Volume: 2023-12-04

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.

DOI: 10.1038/s41588-023-01592-8

Source: https://www.nature.com/articles/s41588-023-01592-8