A preclinical algorithm of soluble surrogate biomarkers that correlate with therapeutic inhibition of the MET oncogene in gastric tumors

Davide Torti, Francesco Sassi, Francesco Galimi, Stefania Gastaldi, Timothy Perera, Paolo M. Comoglio, Livio Trusolino, Andrea Bertotti

Research output: Contribution to journalArticle

Abstract

The MET oncogene is amplified in a fraction of human gastric carcinoma cell lines, with consequent overexpression and constitutive activation of the corresponding protein product, the Met tyrosine kinase receptor. This genetically driven hyperactivation of Met is necessary for cancer cell growth and survival, so that Met pharmacological blockade results in cell-cycle arrest or apoptosis (oncogene addiction). MET gene amplification also occurs in vivo in a number of human gastric carcinomas, and clinical trials are now ongoing to assess the therapeutic efficacy of Met inhibitors in this type of malignancy. The aim of our study was to identify a preclinical algorithm of soluble surrogate biomarkers indicative of response to Met inhibition in gastric tumors, as a potential tool to integrate imaging criteria during patient follow-up. We started from a survey of candidate molecules based on antibody proteomics and gene expression profiling; after ELISA validation and analytical quantification, four biomarkers were identified that appeared to be strongly and consistently modulated by Met inhibition in a panel of Met-addicted gastric carcinoma cell lines, but not in Met-independent cell lines. Pharmacologic blockade of Met using specific small-molecule inhibitors led to reduced secretion of IL-8, GROα and the soluble form of uPAR and to increased production of IL-6 both in vitro (in culture supernatants) and in vivo (in the plasma of xenografted mice). If confirmed in patients, this information might prove useful to monitor clinical response to Met-targeted therapies in MET-amplified gastric carcinomas.

Original languageEnglish
Pages (from-to)1357-1366
Number of pages10
JournalInternational Journal of Cancer
Volume130
Issue number6
DOIs
Publication statusPublished - Mar 15 2012

Keywords

  • Met receptor
  • oncogene addiction
  • surrogate biomarkers
  • targeted therapies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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