Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies.
Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies.
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DOI：
10.1186/1479-5876-11-168
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发表时间：
2013-07-10
影响因子：
7.4
通讯作者：
Wu YL
中科院分区：
文献类型：
--
作者：
Zhang XC;Zhang J;Li M;Huang XS;Yang XN;Zhong WZ;Xie L;Zhang L;Zhou M;Gavine P;Su X;Zheng L;Zhu G;Zhan P;Ji Q;Wu YL
近年来，患者源性肿瘤异种移植模型已被建立并越来越多地用于靶向治疗的临床前研究。然而，患者来源的非小细胞肺癌（NSCLC）异种移植小鼠模型数量相对较少，并且其遗传表征和验证程度有限。在这项研究中，我们的目的是建立各种患者来源的NSCLC模型，并表征这些常见的遗传畸变，为临床前药物疗效测试提供更多信息的模型。收集来自31名患者的NSCLC组织并植入免疫缺陷小鼠中。对建立的异种移植模型进行常见遗传畸变表征，包括检测EGFR和KRAS内的基因突变以及FGFR1和cMET的遗传扩增。最后，在这些患者来源的NSCLC异种移植模型中测试吉非替尼抗肿瘤功效。通过将31例患者的NSCLC标本植入免疫缺陷小鼠体内，建立了10个合格的患者来源的NSCLC异种移植模型。在6个模型中检测到遗传畸变，包括1个EGFR激活突变（Exon19 Del）模型、1个KRAS突变模型、1个KRAS突变和cMET基因扩增模型以及3个FGFR1扩增模型。使用吉非替尼的抗肿瘤疗效研究表明，EGFR激活突变模型具有优越的上级敏感性，KRAS突变模型对吉非替尼耐药。吉非替尼在患者来源的NSCLC异种移植模型中的反应范围与临床试验报告的结果一致。此外，我们观察到FGFR1基因扩增的患者来源的NSCLC模型对吉非替尼治疗不敏感。建立了10个患者来源的NSCLC异种移植物模型，其中包含多种遗传畸变，包括EGFR激活突变、KRAS突变以及FGFR1和cMET扩增。吉非替尼在这些含有EGFR和KRAS突变的患者来源NSCLC异种移植物中的抗肿瘤疗效与既往临床试验报告的结果一致。因此，来自我们的患者来源的NSCLC异种移植模型组的数据证实了这些模型在促进我们对这种疾病的理解和帮助开发NSCLC患者的个性化治疗方面的效用。
Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing. NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models. Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment. Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients.
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