Microscaled proteogenomic methods for precision oncology

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

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.

MeSH terms

  • Biopsy, Large-Core Needle
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Down-Regulation
  • Humans
  • Pilot Projects
  • Proteogenomics / methods*
  • Receptor, ErbB-2 / genetics*
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Trastuzumab / therapeutic use*

Substances

  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab