Microscaled proteogenomic methods for precision oncology

Shankha Satpathy (), Eric J. Jaehnig, Karsten Krug, Beom-Jun Kim, Alexander B. Saltzman, Doug W. Chan, Kimberly R. Holloway, Meenakshi Anurag, Chen Huang, Purba Singh, Ari Gao, Noel Namai, Yongchao Dou, Bo Wen, Suhas V. Vasaikar, David Mutch, Mark A. Watson, Cynthia Ma, Foluso O. Ademuyiwa, Mothaffar F. Rimawi, Rachel Schiff, Jeremy Hoog, Samuel Jacobs, Anna Malovannaya, Terry Hyslop, Karl R. Clauser, D. R. Mani, Charles M. Perou, George Miles, Bing Zhang, Michael A. Gillette, Steven A. Carr () and Matthew J. Ellis ()
Additional contact information
Shankha Satpathy: Broad Institute of Harvard and Massachusetts Institute of Technology
Eric J. Jaehnig: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Karsten Krug: Broad Institute of Harvard and Massachusetts Institute of Technology
Beom-Jun Kim: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Alexander B. Saltzman: Baylor College of Medicine
Doug W. Chan: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Kimberly R. Holloway: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Meenakshi Anurag: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Chen Huang: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Purba Singh: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Ari Gao: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Noel Namai: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Yongchao Dou: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Bo Wen: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Suhas V. Vasaikar: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
David Mutch: Siteman Comprehensive Cancer Center and Washington University School of Medicine
Mark A. Watson: Siteman Comprehensive Cancer Center and Washington University School of Medicine
Cynthia Ma: Siteman Comprehensive Cancer Center and Washington University School of Medicine
Foluso O. Ademuyiwa: Siteman Comprehensive Cancer Center and Washington University School of Medicine
Mothaffar F. Rimawi: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Rachel Schiff: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Jeremy Hoog: Siteman Comprehensive Cancer Center and Washington University School of Medicine
Samuel Jacobs: NSABP Foundation
Anna Malovannaya: Baylor College of Medicine
Terry Hyslop: Duke University Medical Center
Karl R. Clauser: Broad Institute of Harvard and Massachusetts Institute of Technology
D. R. Mani: Broad Institute of Harvard and Massachusetts Institute of Technology
Charles M. Perou: University of North Carolina at Chapel Hill
George Miles: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Bing Zhang: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
Michael A. Gillette: Broad Institute of Harvard and Massachusetts Institute of Technology
Steven A. Carr: Broad Institute of Harvard and Massachusetts Institute of Technology
Matthew J. Ellis: Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14381-2

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