Abstract LB-330: Four individually druggable Met hotspots mediate HGF-driven tumor progression

Abstract

Abstract Activation of Met by HGF plays a key role in tumor progression. Using a newly developed llama platform generating human-like immunoglobulins, we selected 68 different antibodies that competed with HGF for binding to Met. HGF-competing antibodies recognized four hotspots localized in different domains of Met. One hotspot coincides with the previously identified HGF β-chain binding site on blades 2-3 of the SEMA β-propeller. Two hotspots lie within SEMA blade 5 and IPT domains 2-3, respectively, where the HGF α-chain is thought to bind. The last hotspot identifies a new region across the PSI-IPT 1 domains. Individual or combined targeting of these hotspots effectively interrupted HGF-Met signaling in multiple 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 neo-adjuvant 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 providing new molecular tools for targeting Met activity in cancer. Citation Format: Anna Hultberg, Cristina Basilico, Cristophe Blanchetot, Natalie De Jonge, Valérie Hanssens, Gitte De Boeck, Alessia Mira, Manuela Cazzanti, Virginia Morello, Torsten Dreier, Michael Saunders, Hans De Haard, Paolo Michieli. Four individually druggable Met hotspots mediate HGF-driven tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-330. doi:10.1158/1538-7445.AM2014-LB-330