通过MAPK激活和细胞可塑性,在肺腺癌中对EGFRTKI的补充性抵抗模式通过MAPK激活和细胞可塑性
Matthew Zatzman1,2, Alvaro Quintanal-Villalonga3, Sohrab Salehi1,2
1Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
EGFR突变肺癌中耐药性与减少MAPK信号传递和失去腺癌特征有关. 预先存在的瘤细胞可塑性使得EGFR的TKI如 osimertinib.
科学领域:
- 在瘤学瘤学.
- 基因组学就是基因组学.
- 分子生物学分子生物学
背景情况:
- EGFR突变肺腺癌 (LUAD) 是癌症死亡的主要原因之一.
- 目前的EGFR氨酸激酶抑制剂 (TKI) 提供了初步的好处,但往往被药物耐药性所克服.
- 了解耐药机制对于开发有效的LUAD治疗至关重要.
研究的目的:
- 调查与EGFR突变LUAD中获得的对 osimertinib的耐药性相关的基因组和转录组变化.
- 确定驱动瘤进展和EGFR TKI治疗后复发的机制.
主要方法:
- 临床基因组和单核RNA测序数据的综合分析.
- 从62名LUAD患者中比较先前未接受治疗,最小残留疾病和进展性疾病瘤.
- 评估血统忠诚度,MAPK信号和组织学特征.
主要成果:
- 疾病进展与膜系忠诚度降低,MAPK信号减少和腺癌身份丧失相关.
- 低MAPK瘤显示出倾向于组织学转变为状或神经内分泌系.
- 预先存在的,差异化瘤细胞群体与血统可塑性在治疗后扩大,有助于耐药性.
结论:
- 在LUAD中对EGFR TKIs的获得性耐药性涉及基因组编码的MAPK信号改变和谱系可塑性.
- 瘤细胞中的组织学可塑性可能代表了治疗选择的先前存在的基质.
- 针对这些互补的抵抗机制可以改善EGFR突变LUAD患者的结果.
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