激活EGFR中的破坏稳定的Y891D突变会降低对激酶抑制的敏感性
Daniel S Lenchner1,2,3, Zaritza O Petrova4,5, Lisa Hunihan1,2,3
1Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, USA.
NPJ precision oncology
|January 5, 2024
概括
在非小细胞肺癌 (NSCLC) 中,一种新的EGFR Y891D突变通过破坏受体的稳定,而不是通过改变ATP亲和力,导致对氨酸激酶抑制剂 (TKIs) 的耐药性. 这表明蛋白质错误折叠是一种新的抵抗机制.
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:
- 皮表皮生长因子受体 (EGFR) 氨酸激酶抑制剂 (TKI) 是EGFR突变非小细胞肺癌 (NSCLC) 的标准治疗方法.
- 对EGFRTKI的治疗耐药性,通常是由二次EGFR突变驱动的,仍然是一个重要的临床障碍.
研究的目的:
- 为了研究一种新的EGFR Y891D二次变异在NSCLC中,具有现有的EGFR L858R突变.
- 阐明EGFR Y891D对TKI耐药性的作用机制.
主要方法:
- 在患有EGFR L858R的NSCLC患者样本中识别EGFR Y891D突变.
- 使用Ba/F3细胞系进行功能研究,以评估EGFR L858R + Y891D突变的TKI敏感性.
- 分析与Y891D突变相关的ATP亲和力和硬质阻碍.
主要成果:
- EGFR L858R + Y891D 双重突变使得对第一代和第二代 EGFR TKIs 的敏感性降低.
- Y891D突变不会显著改变EGFR的ATP结合亲和力,也不会对TKI结合造成硬质障碍.
- EGFR Y891D似乎会破坏EGFR L858R突变的稳定性,可能导致蛋白质错误折叠.
结论:
- EGFR Y891D可能通过一种涉及蛋白质不稳定和错误折叠的机制,而不是改变ATP亲和力或硬质障碍,赋予TKI耐药性.
- 这一发现表明蛋白质错误折叠是NSCLC中EGFR抑制剂的潜在抵抗机制.
- 对蛋白质错折的进一步研究可能会揭示克服TKI耐药性的新疗法策略.
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