期刊
INTERNATIONAL JOURNAL OF CANCER
卷 143, 期 7, 页码 1774-1785出版社
WILEY
DOI: 10.1002/ijc.31550
关键词
MET oncogene; antibodies; decoy; MET target therapy; anti-HGF therapy
类别
资金
- AIRC IG [15572]
- FPRC 5xMille Ministero della Salute 2013
- FPRC 5xMille Ministero della Salute 2014
- AIRC Special Program 5xMille 2010 MCO [9970]
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). DecoyMET(K842E) retains the ability to bind HGF with high affinity and inhibits HGF-induced MET phosphorylation. In HGF-dependent cellular models, MvDN30 antibody and decoyMET(K842E) 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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