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Nat Commun. 2020 Jan 27;11(1):532. doi: 10.1038/s41467-020-14381-2.

Microscaled proteogenomic methods for precision oncology.

Author information

1
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02142, USA. shankha@broadinstitute.org.
2
Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.
3
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
4
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.
5
Siteman Comprehensive Cancer Center and Washington University School of Medicine, St. Louis, MO, 63110, USA.
6
NSABP Foundation, Pittsburgh, PA, 15212, USA.
7
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, 27710, USA.
8
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27514, USA.
9
Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, 02115, USA.
10
Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, 02142, USA. scarr@broad.mit.edu.
11
Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. Matthew.Ellis@bcm.edu.

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.

PMID:
31988290
PMCID:
PMC6985126
DOI:
10.1038/s41467-020-14381-2
[Indexed for MEDLINE]
Free PMC Article

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