Protein drug target activation homogeneity in the face of intratumor heterogeneity: Implications for precision medicine

Erika Maria Parasido, Alessandra Silvestri, Vincenzo Canzonieri, Claudio Belluco, Maria Grazia Diodoro, Massimo Milione, Flavia Melotti, Ruggero De Maria, Lance Liotta, Emanuel F. Petricoin, Mariaelena Pierobon

Research output: Contribution to journalArticle

Abstract

Introduction: Recent studies indicated tumors may be comprised of heterogeneous molecular subtypes and incongruent molecular portraits may emerge if different areas of the tumor are sampled. This study explored the impact of intratumoral heterogeneity in terms of activation/phosphorylation of FDA approved drug targets and downstream kinase substrates. Material and methods: Two independent sets of liver metastases from colorectal cancer were used to evaluate protein kinase-driven signaling networks within different areas using laser capture microdissection and reverse phase protein array. Results: Unsupervised hierarchical clustering analysis indicated that the signaling architecture and activation of the MAPK and AKT-mTOR pathways were consistently maintained within different regions of the same biopsy. Intra-patient variability of the MAPK and AKT-mTOR pathway were < 1.06 fold change, while inter-patients variability reached fold change values of 5.01. Conclusions: Protein pathway activation mapping of enriched tumor cells obtained from different regions of the same tumor indicated consistency and robustness independent of the region sampled. This suggests a dominant protein pathway network may be activated in a high percentage of the tumor cell population. Given the genomic intra-tumoral variability, our data suggest that protein/phosphoprotein signaling measurements should be integrated with genomic analysis for precision medicine based analysis.

Original languageEnglish
Pages (from-to)48534-48544
Number of pages11
JournalOncotarget
Volume8
Issue number30
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • intra-tumor heterogeneity
  • Kinase signaling
  • Laser capture microdissection
  • Personalized therapy
  • Reverse phase protein microarray

ASJC Scopus subject areas

  • Oncology

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