Microscaled proteogenomic methods for precision oncology.

Nat Commun
Authors
Keywords
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.

Year of Publication
2020
Journal
Nat Commun
Volume
11
Issue
1
Pages
532
Date Published
2020 Jan 27
ISSN
2041-1723
DOI
10.1038/s41467-020-14381-2
PubMed ID
31988290
PubMed Central ID
PMC6985126
Links
Grant list
U24 CA210954 / CA / NCI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
U54 CA233223 / CA / NCI NIH HHS / United States
U24 CA210986 / CA / NCI NIH HHS / United States
P30 CA091842 / CA / NCI NIH HHS / United States
U10 CA180860 / CA / NCI NIH HHS / United States
U24 CA210979 / CA / NCI NIH HHS / United States
U01 CA214125 / CA / NCI NIH HHS / United States
UL1 TR002345 / TR / NCATS NIH HHS / United States