Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.
Proteogenomic integration reveals therapeutic targets in breast cancer xenografts.
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DOI：
10.1038/ncomms14864
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发表时间：
2017-03-28
影响因子：
16.6
通讯作者：
Ding L
中科院分区：
文献类型：
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作者：
Huang KL;Li S;Mertins P;Cao S;Gunawardena HP;Ruggles KV;Mani DR;Clauser KR;Tanioka M;Usary J;Kavuri SM;Xie L;Yoon C;Qiao JW;Wrobel J;Wyczalkowski MA;Erdmann-Gilmore P;Snider JE;Hoog J;Singh P;Niu B;Guo Z;Sun SQ;Sanati S;Kawaler E;Wang X;Scott A;Ye K;McLellan MD;Wendl MC;Malovannaya A;Held JM;Gillette MA;Fenyö D;Kinsinger CR;Mesri M;Rodriguez H;Davies SR;Perou CM;Ma C;Reid Townsend R;Chen X;Carr SA;Ellis MJ;Ding L
质谱（MS）的最新进展使得能够对癌症蛋白质组进行广泛的分析。在这里，我们采用定量蛋白质组学分析了24种乳腺癌患者来源的异种移植物（PDX）模型的蛋白质表达。综合蛋白基因组学分析显示转录组学和蛋白质组学分析的表达测量值之间呈正相关;此外，基于基因表达的内在亚型在很大程度上使用非基质蛋白标志物重新投降。蛋白基因组学分析也验证了多种受体酪氨酸激酶中的许多预测的基因组靶点。然而，一些蛋白质/磷蛋白事件，如AKT蛋白和ARAF，BRAF，HSP 90 AB 1磷酸化位点的过表达是不容易解释的基因组分析，这表明，可药用的翻译和/或翻译后调节事件可能是唯一的MS诊断。药物治疗实验靶向HER 2和PI 3 K通路的组件支持蛋白基因组学反应预测在7个异种移植模型。我们的研究表明，基于MS的蛋白质组学可以识别治疗靶点，并突出了PDX药物反应评价注释基于MS的途径活动的潜力。患者来源的异种移植物概括了其原始肿瘤的主要基因组特征和转录组谱。在这里，作者对24种乳腺癌PDX模型进行了蛋白质组学和磷酸化蛋白质组学分析，证明可以基于全面的蛋白质基因组学分析来鉴定可药用候选物。
Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities. Patient-derived xenografts recapitulate major genomic signatures and transcriptome profiles of their original tumours. Here, the authors, performing proteomic and phosphoproteomic analyses of 24 breast cancer PDX models, demonstrate that druggable candidates can be identified based on a comprehensive proteogenomic profiling.