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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 ? chain binding site on blades 2-3 of the SEMA domain ?-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 ? 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.

SUBMITTER: Basilico C

PROVIDER: S-EPMC4071368 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Four individually druggable MET hotspots mediate HGF-driven tumor progression.

Basilico Cristina C Hultberg Anna A Blanchetot Christophe C de Jonge Natalie N Festjens Els E Hanssens Valérie V Osepa Sjudry-Ilona SI De Boeck Gitte G Mira Alessia A Cazzanti Manuela M Morello Virginia V Dreier Torsten T Saunders Michael M de Haard Hans H Michieli Paolo P

The Journal of clinical investigation 20140527 7

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 with ...[more]

PMID: 24865428

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Dataset Information

Four individually druggable MET hotspots mediate HGF-driven tumor progression.

Publications

Four individually druggable MET hotspots mediate HGF-driven tumor progression.

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