Introduction: NSCLC brain metastasis cell lines and in vivo brain metastasis models are not widely accessible. The purpose of this study was to establish and characterize a direct-from patient-derived xenograft (PDX) model of non-small cell lung cancer (NSCLC) brain metastases. Methods: Surgically obtained tissue was implanted subcutaneously and as orthotopic intracranial implants into immunodeficient mice. Histology and DNA loci were compared between original tumor and subsequent PDX passages. Tumors underwent RNA and DNA sequencing and relevant therapeutic targets were identified. Tumor growth rates were assessed following treatment with radiation, MEK inhibitor selumetinib, or MET inhibitor savolitinib. Cell lines were established. Results: Nine NSCLC brain metastases PDXs were established. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumor and subcutaneous and intracranial tumors. Preservation of thyroid transcription factor 1 expression was seen in all xenografts. Short tandem repeat analysis demonstrated strong concordance between patient tumors and subsequent PDX passages. RNA sequencing analysis revealed high correlation between matched patient and PDX samples. Significant growth inhibition was shown with radiation, with selumetinib in tumors harboring KRAS G12C mutation and with savolitinib in tumors with MET exon 14 skipping mutation. Significant tumor growth delay was observed with the combination of radiation and savolitinib compared to radiation or savolitinib alone in the PDX harboring MET exon 14 skipping mutation. Early passage cell strains showed high consistency between patient and PDX tumors. Conclusion: We have established a robust human xenograft model system for investigating NSCLC brain metastases. These PDXs and cell lines show strong phenotypic and molecular correlation with the original patient tumors and provide a valuable resource for testing preclinical therapeutics.

中文翻译：

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非小细胞肺癌脑转移患者来源异种移植物的开发和表征

简介：NSCLC脑转移细胞系和体内脑转移模型尚未广泛获得。这项研究的目的是建立和表征非小细胞肺癌（NSCLC）脑转移患者直接来自患者的异种移植（PDX）模型。方法：将手术获得的组织皮下植入，并作为原位颅内植入物植入免疫缺陷小鼠中。在原始肿瘤和随后的PDX代之间比较组织学和DNA基因座。对肿瘤进行了RNA和DNA测序，并确定了相关的治疗靶标。放疗，MEK抑制剂selumetinib或MET抑制剂savolitinib治疗后评估肿瘤生长率。建立细胞系。结果：建立了9个NSCLC脑转移PDX。从形态上讲 在原始患者肿瘤与皮下和颅内肿瘤之间观察到强的细胞结构特征保留。在所有异种移植物中均观察到了甲状腺转录因子1表达的保存。短串联重复分析表明，患者肿瘤与随后的PDX代之间存在高度一致性。RNA测序分析显示，匹配的患者和PDX样品之间具有高度相关性。辐射显示出显着的生长抑制作用，在具有KRAS G12C突变的肿瘤中使用selumetinib，在具有MET外显子14跳跃突变的肿瘤中显示有savolitinib。在携带MET外显子14跳跃突变的PDX中，与单独使用放射线或savolitinib相比，使用放射线和savolitinib的组合观察到明显的肿瘤生长延迟。早期传代细胞株显示患者和PDX肿瘤之间的高度一致性。结论：我们已经建立了一个强大的人类异种移植模型系统，用于研究NSCLC脑转移。这些PDX和细胞系显示出与原始患者肿瘤的强表型和分子相关性，并为测试临床前疗法提供了宝贵的资源。