| First Author | Basilico C | Year | 2014 |
| Journal | J Clin Invest | Volume | 124 |
| Issue | 7 | Pages | 3172-86 |
| PubMed ID | 24865428 | Mgi Jnum | J:213196 |
| Mgi Id | MGI:5583887 | Doi | 10.1172/JCI72316 |
| Citation | Basilico C, et al. (2014) Four individually druggable MET hotspots mediate HGF-driven tumor progression. J Clin Invest 124(7):3172-86 |
| abstractText | 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 beta chain binding site on blades 2-3 of the SEMA domain beta-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 alpha 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. |
