Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation
Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation
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DOI：
10.1016/j.lungcan.2018.08.008
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发表时间：
2018-10-01
期刊：
影响因子：
5.3
通讯作者：
Kim, Hye Ryun
中科院分区：
文献类型：
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作者：
Kang, Han Na;Choi, Jae Woo;Kim, Hye Ryun
背景资料：在这个个性化癌症治疗的时代，需要能够更好地预测临床试验中治疗活性的临床前模型。在此，我们建立了基因组学和临床注释的患者来源的异种移植物（PDXs）从非小细胞肺癌（NSCLC）患者，并调查这些PDXs是否会忠实地概括患者的反应，靶向therapy.Methods：患者来源的肿瘤被植入免疫缺陷小鼠，随后通过重新植入扩大。通过光学显微镜、基因组分析和体内药物测试来检查已建立的PDX，并通过突变谱、组织学或采集方法来分析成功的植入率。最后，将PDX的药物反应与相应患者的临床反应进行比较。结果：使用来自122名患者的样本，我们建立了41个NSCLC PDX [30个腺癌（AD），11个鳞状细胞癌（SQ）]，其中观察到以下驱动突变：13例EGFR突变、4例ALK重排、1例ROS 1重排、1例PIK 3CA突变、1例FGFR 1扩增和2例KRAS突变。我们严格描述了临床特征与植入率和潜伏率的关系。不同组织学类型的植入率相当。相对于活检，手术切除组织的AD移植率往往更高，而无论采集方法如何，SQ的移植率相似。值得注意的是，EGFR突变体表现出比EGFR-WT显著更长的潜伏期（86 vs. 37天，P = 0.007）。临床反应被概括的PDXs窝藏驱动基因改变（EGFR，ALK，ROS 1，或FGFR 1）回归到他们的目标抑制剂，这表明，建立PDXs包括临床相关platform.Conclusion：建立基因和临床注释的NSCLC PDXs可以产生一个强大的临床前生物标志物，治疗靶点和药物发现的工具。
Background: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy.Methods: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients.Results: Using samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform.Conclusion: The establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.