Abstract 828: Targeting the MET oncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy

Abstract

Abstract Background: MET, a master gene sustaining ‘invasive growth', is a relevant target for cancer precision therapy. In a limited number of cases, a MET genetic lesion drives the malignant phenotype in ligand-independent manner (oncogene ‘addiction'). In the vast majority of tumors, however, 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 -i.e. ligand-dependent MET activation- concomitant targeting of MET and HGF could be crucial to reach effective inhibition. Methods: To test this hypothesis we combined an anti-MET antibody (MvDN30), characterized by the property of 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 by site directed mutagenesis a single aminoacid in the extracellular domain of MET -lysine 842- that is critical for MvDN30 binding, and engineered the corresponding recombinant decoyMET (K842E). The effect of MvDN30 and decoyMETK842E in combination on the inhibition of MET phosphorylation and on the impairment of different MET driven biological responses (motility, invasion, cell proliferation, apoptosis and anchorage independent cell growth) was evaluated on a panel of cancer cells (lines and patient derived-primary cultures) expressing wild-type MET sensitive to HGF stimulation. Therapeutic efficacy was assessed in an orthotopic model of pancreatic cancer generated in SCID mice engineered to express human HGF. Results: The 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 the preclinical model of MET ‘expedience' concomitant treatment with antibody and decoy significantly reduces metastatic spread. Conclusions: 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 targeted therapy of MET ‘expedience'. Citation Format: Cristina Basilico, Chiara Modica, Federica Maione, Elisa Vigna, Paolo M. Comoglio. Targeting the MET oncogene by concomitant inhibition of receptor and ligand by an antibody-‘decoy' strategy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 828.