Microscaled proteogenomic methods for precision oncology

• Published in: Nature communications Vol. 11; no. 1; p. 532
• Main Authors: Satpathy, Shankha, Jaehnig, Eric J, Krug, Karsten, Kim, Beom-Jun, Saltzman, Alexander B, Chan, Doug W, Holloway, Kimberly R, Anurag, Meenakshi, Huang, Chen, Singh, Purba, Gao, Ari, Namai, Noel, Dou, Yongchao, Wen, Bo, Vasaikar, Suhas V, Mutch, David, Watson, Mark A, Ma, Cynthia, Ademuyiwa, Foluso O, Rimawi, Mothaffar F, Schiff, Rachel, Hoog, Jeremy, Jacobs, Samuel, Malovannaya, Anna, Hyslop, Terry, Clauser, Karl R, Mani, D R, Perou, Charles M, Miles, George, Zhang, Bing, Gillette, Michael A, Carr, Steven A, Ellis, Matthew J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.01.2020; Nature Publishing Group UK; Nature Portfolio
• Subjects: Amplification; Androgen receptors; Biopsy; Biopsy, Large-Core Needle; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cancer; Cancer therapies; Chemotherapy; Down-Regulation; ErbB-2 protein; Genomics; Humans; Mass spectrometry; Mass spectroscopy; Monoclonal antibodies; Mucin; Oncology; Pilot Projects; Precision medicine; Proteins; Proteogenomics - methods; Proteomics; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Signal Transduction; Signaling; Targeted cancer therapy; TOR protein; TOR Serine-Threonine Kinases - genetics; TOR Serine-Threonine Kinases - metabolism; Trastuzumab; Trastuzumab - therapeutic use
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-14381-2

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.