Microscaled proteogenomic methods for precision oncology
Microscaled proteogenomic methods for precision oncology
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DOI：
10.1038/s41467-020-14381-2
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发表时间：
2020-01-27
影响因子：
16.6
通讯作者：
Ellis, Matthew J.
中科院分区：
文献类型：
--
作者：
Satpathy, Shankha;Jaehnig, Eric J.;Ellis, Matthew J.
癌症蛋白基因组学通过整合基因组学、转录组学和蛋白质谱分析（包括质谱（MS）修饰），为癌症生物学和治疗效果提供了新的见解。一个关键的限制是样本输入要求超过了许多临床重要材料的来源。在这里，我们报告了一个蛋白质组学的核心活检方法，使用组织保留标本处理和微型蛋白质组学。作为示范，我们分析了ERBB 2阳性乳腺癌在开始新辅助曲妥珠单抗化疗之前和之后48- 72小时的空芯针活检。我们发现，在与病理完全缓解相关的病例中，ERBB 2蛋白以及ERBB 2和mTOR靶磷酸化位点水平受到更大的抑制，并确定了治疗耐药的潜在原因，包括缺乏ERBB 2扩增，尽管ERBB 2扩增，但ERBB 2活性对治疗敏感性不足，以及候选耐药机制，包括雄激素受体信号传导，粘蛋白过表达和非活性免疫微环境。蛋白质组学在活检规模的临床应用和发现潜力值得进一步研究。
Cancer proteogenomics promises new insights into cancer biology and treatment efficacy by integrating genomics, transcriptomics and protein profiling including modifications by mass spectrometry (MS). A critical limitation is sample input requirements that exceed many sources of clinically important material. Here we report a proteogenomics approach for core biopsies using tissue-sparing specimen processing and microscaled proteomics. As a demonstration, we analyze core needle biopsies from ERBB2 positive breast cancers before and 48-72h after initiating neoadjuvant trastuzumab-based chemotherapy. We show greater suppression of ERBB2 protein and both ERBB2 and mTOR target phosphosite levels in cases associated with pathological complete response, and identify potential causes of treatment resistance including the absence of ERBB2 amplification, insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification, and candidate resistance mechanisms including androgen receptor signaling, mucin overexpression and an inactive immune microenvironment. The clinical utility and discovery potential of proteogenomics at biopsy-scale warrants further investigation.