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针对性治疗的混合反应是由通过p53功能障碍和基因组翻一番的染色体不稳定性驱动的
Sebastijan Hobor1, Maise Al Bakir1, Crispin T Hiley1,2,3
1Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Nature communications
|June 13, 2024
概括
患有肺腺癌和EGFR/TP53共同突变的患者对EGFR氨酸激酶抑制剂 (TKI) 呈现混合反应. 整个基因组的翻一番与TP53突变相结合,通过增加基因组不稳定性来驱动耐药性.
科学领域:
- 在瘤学瘤学.
- 遗传学 遗传学 是一个
- 分子生物学分子生物学
背景情况:
- 癌症患者的混合或异质治疗反应带来临床挑战.
- 患者内瘤异质性的分子基础在很大程度上是未知的.
研究的目的:
- 为了研究转移性肺腺癌中EGFR氨酸激酶抑制 (TKI) 的混合患者内瘤反应的分子基础.
- 探索共突变和基因组改变在治疗耐药性的作用.
主要方法:
- 对具有单独EGFR突变的肺腺癌患者与EGFR和TP53共同突变进行比较分析.
- 利用小鼠模型和体外同源的p53突变细胞系统.
- 评估全基因组倍增 (WGD) 对基因组不稳定性和基因拷贝数量的改变的影响.
主要成果:
- 与具有单独EGFR突变的患者相比,同时发生EGFR和TP53突变的患者对EGFR TKI的混合患者内反应的可能性更高.
- 结合WGD和TP53共同突变,显著增加了与EGFRTKI耐药性相关的基因中的基因不稳定性和拷贝数异常.
- 通过提高获取副本数量增长或损失的概率,WGD促进了多样化的阻力机制.
结论:
- 为接受向治疗的个体患者中异质瘤反应提供了分子解释.
- 突出了WGD和TP53共同突变在推动肺腺癌中EGFR TKI耐药性的关键作用.
- 建议在具有复杂基因组特征的患者中改进治疗策略的含义.
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