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在PDX模型中MET通路激活的功能异质性,对Osimertinib耐药EGFR驱动的肺癌的PDX模型

Nitin Roper¹, Rajaa El Meskini², Tapan Maity³

¹Developmental Therapeutics Branch, Center for Cancer Research, NCI, Bethesda, Maryland.

Cancer research communications

|January 26, 2024

概括

在EGFR突变肺癌中,MET通路的激活驱动了对 osimertinib 的耐药性. -MET测试可以指导与 osimertinib 和 savolitinib 的联合治疗,以改善患者的治疗结果.

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:

MET通路激活是EGFR突变非小细胞肺癌 (NSCLC) 中对奥西默提尼布的常见耐药机制.
以前的研究表明MET途径激活的空间和时间异质性,但其临床相关性仍然不清楚.

研究的目的:

为了研究MET途径激活异质性在异星丁尼布耐药性的功能相关性.
在患者衍生异种移植 (PDX) 模型中评估联合奥西默蒂尼布与萨沃利提尼布的疗效,以评估具有获得性耐药性的EGFR突变NSCLC.

主要方法:

从9名患者中生成了19个PDX模型,采用了多区域和时间样本,采集了耐奥西默提尼布的瘤组织.
使用FISH对MET放大和-MET免疫组织化学 (IHC) 的评估MET通路激活.
在PDX模型中,对单独的奥西默蒂尼布和组合治疗的评估反应.

主要成果:

在66%的PDX模型中确定了MET通路激活,显示出显著的空间和时间异质性.
具有MET放大 (FISH) 和高-MET的PDX对奥西默蒂尼布加萨沃利提尼布的反应比单独对奥西默蒂尼布的反应更好.
即使具有亚克隆基MET表达的MET多体瘤,也对组合疗法反应有所改善.

结论:

-MET测试是一种临床相关的生物标志物,用于指导用 osimertinib 和 savolitinib 联合治疗的治疗选择.
瘤中的MET多体可能表明亚克隆MET放大,需要密切监测和-MET IHC与FISH诊断并行.

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