title: A preclinical algorithm of soluble surrogate biomarkers that correlate with therapeutic inhibition of the MET oncogene in gastric tumors.
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.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Torino, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Torti
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Stefania
authors.initials: S
authors.lastname: Gastaldi
authors.forename: Timothy
authors.initials: T
authors.lastname: Perera
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000097:blood / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D040901:Proteomics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics / Q000378:metabolism; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D014408:Biomarkers, Tumor; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C508600:IL6 protein, human; D007211:Indoles; D015850:Interleukin-6; D016209:Interleukin-8; C404106:MRC2 protein, human; D037241:Mannose-Binding Lectins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D013450:Sulfones; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met