Department of Molecular Biotechnology and Health Science and Center for Experimental Research and Medical Studies, University of Turin, Torino, Italy; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, 10021, USA.
Department of Thoracic Surgery, University of Turin, A.O.U. Città della Salute e della Scienza di Torino, Torino, Italy.
Eur J Cancer. 2021 Feb;144:17-30. doi: 10.1016/j.ejca.2020.10.036. Epub 2020 Dec 11.
High fidelity between non-small cell lung cancer (NSCLC) primary tumours and patient-derived tumour xenografts (PDTXs) is of paramount relevance to spur their application. Extensive proteomic and kinomic analysis of these preclinical models are missing and may inform about their functional status, in terms of phosphopeptides and hyperactive signalling pathways.
We investigated tumour xenografts derived from patients with NSCLC to identify hyperactive signalling pathways. Fresh tumour fragments from 81 NSCLC surgical samples were implanted in Nod/Scid/Gamma mice, and engrafted tumours were compared with primary specimens by morphology, immunohistochemistry, gene mutation analyses, and kinase activity profiling. Four different tyrosine and serine/threonine kinase inhibitors were tested against primary tumour and PDTX lysates using the PamGene peptide microarray platform.
The engraftment rate was 33%, with successful engraftment being more associated with poor clinical outcomes. Genomic profiles led to the recognition of hotspot mutations, some of which were initially undetected in donor samples. Kinomic analyses showed that characteristics of primary tumours were retained in PDTXs, and tyrosine kinase inhibitors (TKIs) responses of individual PDTX lines were either expected, based on the genetic status, or alternatively defined suitable targets unpredictable by single-genome fingerprints.
Collectively, PDTXs mostly resembled their parental NSCLC. Combining genomic and kinomic analyses of tumour xenografts derived from patients with NSCLC, we identified patients' specific targetable pathways, confirming PDTXs as a preclinical tool for biomarker identification and therapeutic algorithm'' improvement.
非小细胞肺癌（NSCLC）原发肿瘤与患者来源的肿瘤异种移植物（PDTXs）之间具有高度的一致性，这对于推动它们的应用至关重要。这些临床前模型的广泛蛋白质组学和激酶组学分析缺失，可能会根据磷酸肽和过度活跃的信号通路来提供其功能状态的信息。
我们研究了源自 NSCLC 患者的肿瘤异种移植物，以确定过度活跃的信号通路。从 81 例 NSCLC 手术样本中取出新鲜的肿瘤碎片，植入 Nod/Scid/Gamma 小鼠中，通过形态学、免疫组织化学、基因突变分析和激酶活性谱分析，比较移植瘤与原发标本。使用 PamGene 肽微阵列平台，针对原发性肿瘤和 PDTX 裂解物，测试了四种不同的酪氨酸和丝氨酸/苏氨酸激酶抑制剂。
植入率为 33%，成功植入与较差的临床结果更相关。基因组图谱导致识别热点突变，其中一些突变最初在供体样本中未检测到。激酶组学分析表明，PDTXs 保留了原发性肿瘤的特征，并且个体 PDTX 系对酪氨酸激酶抑制剂（TKIs）的反应要么是基于遗传状态预期的，要么通过单基因组指纹预测不可预测的合适靶标。
总的来说，PDTXs 大多与它们的母本 NSCLC 相似。通过对源自 NSCLC 患者的肿瘤异种移植物进行基因组和激酶组学分析，我们确定了患者可靶向的特定途径，证实了 PDTXs 是一种用于生物标志物识别和治疗算法改进的临床前工具。
