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. RimawiRachel 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, Matthew J. Ellis

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish
Article number532
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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  • Cite this

    Satpathy, S., Jaehnig, E. J., Krug, K., Kim, B. J., Saltzman, A. B., Chan, D. W., Holloway, K. R., Anurag, M., Huang, C., Singh, P., Gao, A., Namai, N., Dou, Y., Wen, B., Vasaikar, S. V., Mutch, D., Watson, M. A., Ma, C., Ademuyiwa, F. O., ... Ellis, M. J. (2020). Microscaled proteogenomic methods for precision oncology. Nature communications, 11(1), [532]. https://doi.org/10.1038/s41467-020-14381-2