Department of Medicine, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
McDonnell Genome Institute, Washington University in St. Louis, St. Louis, Missouri 63108, USA.
Nat Commun. 2017 Mar 28;8:14864. doi: 10.1038/ncomms14864.
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.
近年来，质谱（MS）技术的发展使得对癌症蛋白质组的广泛分析成为可能。在这里，我们采用定量蛋白质组学方法对 24 种乳腺癌患者来源的异种移植（PDX）模型中的蛋白质表达进行了分析。综合蛋白质基因组分析表明，转录组和蛋白质组分析的表达测量之间存在正相关；此外，使用非基质蛋白标志物很大程度上再现了基于基因表达的内在亚型。蛋白质基因组分析还验证了多个受体酪氨酸激酶中许多预测的基因组靶标。然而，一些蛋白质/磷酸蛋白质事件，如 AKT 蛋白和 ARAF、BRAF、HSP90AB1 磷酸化位点的过表达，不能通过基因组分析得到很好的解释，这表明可用药的翻译后和/或翻译后调节事件可能可以通过 MS 进行独特诊断。针对 HER2 和 PI3K 通路成分的药物治疗实验支持了七种异种移植模型中基于蛋白质组学的反应预测。我们的研究表明，基于 MS 的蛋白质组学可以鉴定治疗靶点，并强调了 PDX 药物反应评估来注释基于 MS 的途径活性的潜力。
