A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity

摘要: Simultaneous targeting of epidermal growth factor receptor (EGFR) and Met in cancer therapy is under pre-clinical clinical evaluation. Here, we report the finding that treatment with EGFR inhibitors various tumor cells, when stimulated hepatocyte (HGF) EGF, results transient upregulation phosphorylated AKT. Furthermore, inhibition this setting stimulates a pro-invasive phenotype as assessed Matrigel-based assays. AKT abrogates invasive growth, hence functionally linking signaling phenotype. This observation implies during tumors balanced ratio required. To address this, designed bispecific antibody Met, which has advantage fixed 2:1 stoichiometry. inhibits proliferation cell cultures co-cultures fibroblasts an additive manner compared both single agents. In addition, migration assays reveal higher potency comparison antibodies' combination at low doses. We demonstrate specifically observed cetuximab. Finally, potently non-small lung xenograft model bearing strong autocrine HGF-loop. Together, our findings strongly support further evaluation resistance mechanisms to context active signaling.