TY - JOUR
T1 - Microscaled proteogenomic methods for precision oncology
AU - Satpathy, Shankha
AU - Jaehnig, Eric J.
AU - Krug, Karsten
AU - Kim, Beom Jun
AU - Saltzman, Alexander B.
AU - Chan, Doug W.
AU - Holloway, Kimberly R.
AU - Anurag, Meenakshi
AU - Huang, Chen
AU - Singh, Purba
AU - Gao, Ari
AU - Namai, Noel
AU - Dou, Yongchao
AU - Wen, Bo
AU - Vasaikar, Suhas V.
AU - Mutch, David
AU - Watson, Mark A.
AU - Ma, Cynthia
AU - Ademuyiwa, Foluso O.
AU - Rimawi, Mothaffar F.
AU - Schiff, Rachel
AU - Hoog, Jeremy
AU - Jacobs, Samuel
AU - Malovannaya, Anna
AU - Hyslop, Terry
AU - Clauser, Karl R.
AU - Mani, D. R.
AU - Perou, Charles M.
AU - Miles, George
AU - Zhang, Bing
AU - Gillette, Michael A.
AU - Carr, Steven A.
AU - Ellis, Matthew J.
N1 - Funding Information:
This work was done in collaboration with the U.S. National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC) and supported by grants NIH/NCI U24-CA210986 (to S.A.C. and M.A.G.), NIH/NCI U01 CA214125 (to S.A.C. and M.J. E.), NIH/NCI U24CA210979 (to D.R.M.), NIH/NCI U24 CA210954 (to B.Z.), NIH/ NCI U10 CA180860 (to D.M. and M.J.E.) and NIH/NCI U54CA233223 (M.J.E.). Tissue acquisition was partly supported by the Breast Cancer Research Foundation (BCRF) grant to M.J.E. M.J.E. was also supported by Cancer Prevention & Research Institutes of Texas Scholar (CPRIT) established investigator recruitment award CPRIT RR140033. M.J.E. is a Susan G. Komen Scholar and McNair Medical Foundation Fellow and B.Z. is a Cancer Prevention & Research Institutes of Texas Scholar in Cancer Research (CPRIT RR160027) and McNair Medical Institute Scholar. The authors would like to thank Broad Genomics platform for their assistance with genomic sequencing, Shayan Avanessian and Michael Burgess for technical support and Rena Mao for help with immunohistochemistry. We also thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO. and the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis, for the use of the Tissue Procurement Core, which provided clinical cores. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA091842 and the ICTS is funded by the National Institutes of Health’s NCATS Clinical and Translational Science Award (CTSA) program grant #UL1 TR002345. All subjects provided written consent to research according to a protocol approved by human subjects research boards at the institutions where the patients were accrued. Animal research was conducted under a Protocol approved and monitored by the Baylor College of Medicine Animal Use and Care Committee. This study was also approved by an institutional review board committee at Broad Institute, Baylor School of Medicine and University of Washington at St. Louis, and the NSABP Foundation. Inc. All patients provided consent for proteogenomics analyses.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078365239&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-14381-2
DO - 10.1038/s41467-020-14381-2
M3 - Article
C2 - 31988290
AN - SCOPUS:85078365239
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 532
ER -