APOBEC3B在肺瘤进化和向癌症治疗耐药性的作用
Deborah R Caswell1, Philippe Gui2, Manasi K Mayekar2
1Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. deborah.caswell@crick.ac.uk.
Nature genetics
|December 4, 2023
概括
类似于阿波利波蛋白B mRNA编辑催化子单元 (APOBEC) 的酶APOBEC3B (A3B) 对肺癌产生影响. A3B可以阻碍瘤生长,但也会导致对EGFR向治疗的耐药性,这表明它是潜在的治疗点.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 由表皮生长因子受体 (EGFR) 驱动的非小细胞肺癌 (NSCLC) 是一个主要的健康问题.
- 针对EGFR的向治疗改善了患者的治疗结果,但耐药性仍然是一个挑战.
- 越来越多地认识到阿波利波蛋白B mRNA编辑催化子单元类 (APOBEC) 酶在癌症中的作用,特别是APOBEC3B (A3B).
研究的目的:
- 研究APOBEC3B (A3B) 对EGFR驱动的非小细胞肺癌 (NSCLC) 的影响.
- 确定A3B表达和对NSCLCEGFR向治疗的反应之间的关联.
- 确定针对A3B的潜在治疗策略,以提高治疗疗效.
主要方法:
- 利用EGFR突变 (EGFRmut) NSCLC小鼠模型来评估A3B对瘤发生的作用.
- 分析了人类NSCLC模型和EGFR向治疗的患者样本.
- 研究了核因子kappa B (NF-κB) 在调节A3B表达中的作用.
- 评估了A3B缺乏对癌细胞活力和突变特征的影响.
主要成果:
- 在EGFRmut NSCLC小鼠模型中,A3B表达限制了瘤发生.
- 在NSCLC中,A3B表达与对EGFR向治疗的耐药性有关.
- 人类NSCLC模型在EGFR向治疗时显示A3B上调,由治疗激活的NF-κB诱导.
- A3B 缺陷显著降低了活力,并且对于经过治疗的 NSCLC 模型中的 APOBEC 突变特征至关重要.
- 在接受EGFR向治疗的NSCLC患者中证实了A3B上调.
结论:
- APOBEC3B (A3B) 在EGFR驱动的NSCLC中起着双重作用,可能抑制初始瘤生长,但促进对向疗法的耐药性.
- 治疗诱导的NF-κB激活升高了A3B的调节,从而导致治疗耐药性.
- 向A3B可能是一个新的策略,以克服耐药性,并实现更持久的反应EGFR向癌症治疗在NSCLC患者.
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