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 48-72 h 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.

中文翻译：

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用于精确肿瘤学的微尺度蛋白质组学方法。

癌症蛋白质组学通过整合基因组学、转录组学和蛋白质分析（包括通过质谱 (MS) 进行的修饰），有望对癌症生物学和治疗效果有新的认识。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，我们报告了一种使用组织保留标本处理和微尺度蛋白质组学进行核心活检的蛋白质组学方法。作为示范，我们分析了 ERBB2 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 小时的核心针活检。在与病理学完全反应相关的病例中，我们显示出对 ERBB2 蛋白和 ERBB2 和 mTOR 靶磷酸盐水平的更大抑制，并确定了治疗耐药性的潜在原因，包括 ERBB2 扩增的缺失，尽管 ERBB2 扩增，但 ERBB2 活性不足以治疗敏感性，以及候选耐药机制包括雄激素受体信号转导、粘蛋白过度表达和不活跃的免疫微环境。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。