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: Cristina Basilico, Anna Hultberg, Christophe Blanchetot, Natalie de Jonge, Els Festjens, Valérie Hanssens, Sjudry-Ilona Osepa, Gitte De Boeck, Alessia Mira, Manuela Cazzanti, Virginia Morello, Torsten Dreier, Michael Saunders, Hans de Haard, Paolo Michieli
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 124 Issue 7 Pg. 3172-86 (Jul 2014) ISSN: 1558-8238 [Electronic] United States
• PMID: 24865428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• HGF protein, human
• HGF protein, mouse
• Hepatocyte Growth Factor
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antibodies, Monoclonal
• Antibody Affinity
• Binding Sites
• Binding, Competitive
• Brain Neoplasms (genetics, metabolism, pathology)
• Camelids, New World
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Glioblastoma (genetics, metabolism, pathology)
• Hepatocyte Growth Factor (chemistry, immunology, metabolism)
• Humans
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Models, Molecular
• Protein Interaction Domains and Motifs
• Proto-Oncogene Proteins c-met (chemistry, genetics, metabolism)