Microscaled Proteogenomic Methods for Precision Oncology
Eric J Jaehnig,
Alexander B. Saltzman,
Kimberly R Holloway,
Foluso O. Ademuyiwa,
Karl C Clauser,
D. R. Mani,
Michael A. Gillette,
Steven A. Carr,
Matthew J. Ellis
Posted 08 Oct 2019
bioRxiv DOI: 10.1101/796318 (published DOI: 10.1038/s41467-020-14381-2)
Posted 08 Oct 2019
Cancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a “microscaled” proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumab-based chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated.
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