title: Four individually druggable MET hotspots mediate HGF-driven tumor progression.
abstract: Activation of MET by HGF plays a key role in tumor progression. Using a recently developed llama platform that generates human-like immunoglobulins, we selected 68 different antibodies that compete with HGF for binding to MET. HGF-competing antibodies recognized 4 distinct hotspots localized in different MET domains. We identified 1 hotspot that coincides with the known HGF β chain binding site on blades 2-3 of the SEMA domain β-propeller. We determined that a second and a third hotspot lie within blade 5 of the SEMA domain and IPT domains 2-3, both of which are thought to bind to HGF α chain. Characterization of the fourth hotspot revealed a region across the PSI-IPT 1 domains not previously associated with HGF binding. Individual or combined targeting of these hotspots effectively interrupted HGF/MET signaling in multiple cell-based biochemical and biological assays. Selected antibodies directed against SEMA blades 2-3 and the PSI-IPT 1 region inhibited brain invasion and prolonged survival in a glioblastoma multiforme model, prevented metastatic disease following neoadjuvant therapy in a triple-negative mammary carcinoma model, and suppressed cancer cell dissemination to the liver in a KRAS-mutant metastatic colorectal cancer model. These results identify multiple regions of MET responsible for HGF-mediated tumor progression, unraveling the complexity of HGF-MET interaction, and provide selective molecular tools for targeting MET activity in cancer.
authors.forename: Cristina
authors.initials: C
authors.lastname: Basilico
authors.forename: Anna
authors.initials: A
authors.lastname: Hultberg
authors.forename: Christophe
authors.initials: C
authors.lastname: Blanchetot
authors.forename: Natalie
authors.initials: N
authors.lastname: de Jonge
authors.forename: Els
authors.initials: E
authors.lastname: Festjens
authors.forename: Valérie
authors.initials: V
authors.lastname: Hanssens
authors.forename: Sjudry-Ilona
authors.initials: SI
authors.lastname: Osepa
authors.forename: Gitte
authors.initials: G
authors.lastname: De Boeck
authors.forename: Alessia
authors.initials: A
authors.lastname: Mira
authors.forename: Manuela
authors.initials: M
authors.lastname: Cazzanti
authors.forename: Virginia
authors.initials: V
authors.lastname: Morello
authors.forename: Torsten
authors.initials: T
authors.lastname: Dreier
authors.forename: Michael
authors.initials: M
authors.lastname: Saunders
authors.forename: Hans
authors.initials: H
authors.lastname: de Haard
authors.forename: Paolo
authors.initials: P
authors.lastname: Michieli
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000915:Antibody Affinity; D001665:Binding Sites; D001667:Binding, Competitive; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002161:Camelids, New World; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D019859:Proto-Oncogene Proteins c-met / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C066855:HGF protein, human; C553307:HGF protein, mouse; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met