Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.
Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts.
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DOI：
10.1158/2159-8290.cd-17-0935
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发表时间：
2018-05
期刊：
影响因子：
28.2
通讯作者：
Farago AF
中科院分区：
文献类型：
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作者：
Drapkin BJ;George J;Christensen CL;Mino-Kenudson M;Dries R;Sundaresan T;Phat S;Myers DT;Zhong J;Igo P;Hazar-Rethinam MH;Licausi JA;Gomez-Caraballo M;Kem M;Jani KN;Azimi R;Abedpour N;Menon R;Lakis S;Heist RS;Büttner R;Haas S;Sequist LV;Shaw AT;Wong KK;Hata AN;Toner M;Maheswaran S;Haber DA;Peifer M;Dyson N;Thomas RK;Farago AF
小细胞肺癌(SCLC)患者来源的异种移植(PDX)可以由活检或循环肿瘤细胞(CTC)产生，尽管组织稀缺和肿瘤生长效率低以前限制了这些方法。应用已建立的用于组织收集的临床-翻译管道和用于CTC浓缩的自动化微流控平台，我们在两年时间内生成了17个来自活检组织的PDX和17个来自CTC的PDX，效率分别为89%和38%。全外显子组测序显示，患者肿瘤和PDX之间的体细胞变化稳定保持。早期传代的PDX维持创始人PDX的基因组和转录图谱。在30个PDX模型中，依托泊苷和铂(EP)的活体治疗显示，来自EP初治患者的PDX对EP更敏感，EP的抵抗对应于MYC基因信号表达的增加。最后，从单个患者在多个时间点产生的一系列CTC衍生的PDX准确地概括了该患者疾病不断演变的药物敏感性。总体而言，这项工作突出了这一战略的翻译潜力。
Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient’s disease. Collectively, this work highlights the translational potential of this strategy.