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Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody-"decoy" strategy.
Basilico, Cristina; Modica, Chiara; Maione, Federica; Vigna, Elisa; Comoglio, Paolo M.
Afiliação
  • Basilico C; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
  • Modica C; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
  • Maione F; Department of Oncology, University of Turin, Torino, Italy.
  • Vigna E; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
  • Comoglio PM; Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.
Int J Cancer ; 143(7): 1774-1785, 2018 10 01.
Article em En | MEDLINE | ID: mdl-29693242
ABSTRACT
MET, a master gene sustaining "invasive growth," is a relevant target for cancer precision therapy. In the vast majority of tumors, wild-type MET behaves as a "stress-response" gene and relies on the ligand (HGF) to sustain cell "scattering," invasive growth and apoptosis protection (oncogene "expedience"). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti-MET antibody (MvDN30) inducing "shedding" (i.e., removal of MET from the cell surface), with a "decoy" (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF-sequestering ability. To avoid antibody/decoy interaction-and subsequent neutralization-we identified a single aminoacid in the extracellular domain of MET-lysine 842-that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMETK842E retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMETK842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell "scattering." The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand-dependent MET activation, providing proof of concept in favor of combined target therapy of MET "expedience."
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias do Colo / Glioblastoma / Proteínas Proto-Oncogênicas c-met / Neoplasias Pulmonares / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias do Colo / Glioblastoma / Proteínas Proto-Oncogênicas c-met / Neoplasias Pulmonares / Anticorpos Monoclonais Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article