Four individually druggable MET hotspots mediate HGF-driven tumor progression

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)3172-3186
Number of pages15
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
Publication statusPublished - Jul 1 2014

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Four individually druggable MET hotspots mediate HGF-driven tumor progression'. Together they form a unique fingerprint.

  • Cite this

    Basilico, C., Hultberg, A., Blanchetot, C., De Jonge, N., Festjens, E., Hanssens, V., Osepa, S. I., De Boeck, G., Mira, A., Cazzanti, M., Morello, V., Dreier, T., Saunders, M., De Haard, H., & Michieli, P. (2014). Four individually druggable MET hotspots mediate HGF-driven tumor progression. Journal of Clinical Investigation, 124(7), 3172-3186. https://doi.org/10.1172/JCI72316