Targeting the HGF/Met signaling pathway in cancer therapy

Abstract

Introduction: Under normal conditions, hepatocyte growth factor (HGF)-induced activation of its cell surface receptor, the Met tyrosine kinase (TK), is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand-activated receptor internalization and degradation. Despite these controls, HGF/Met signaling contributes to oncogenesis and tumor progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumor metastasis.

Area covered: The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programs. The authors review Met structure and function, the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development, as well as the latest clinical trial results.

Expert opinion: Clinical trials with HGF/Met pathway antagonists show that as a class these agents are well tolerated. Although widespread efficacy was not seen in several completed Phase II studies, promising results have been reported in lung, gastric, prostate and papillary renal cancer patients treated with these agents. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment are optimal patient selection, diagnostic and pharmacodynamic biomarker development, and the identification and testing of optimal therapy combinations. The wealth of basic information, analytical reagents, and model systems available concerning HGF/Met oncogenic signaling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.

Figure 1. Met domain structure and routes to antagonize the HGF/Met pathway

A. Schematic of Met domain structure; domain lengths are proportional to number of constituent amino acid residues. Mature Met is a disulfide-linked two chain heterodimer with an extracellular amino terminal α-chain (45 kDa) and a carboxyl terminal β-chain (145 kDa) containing extracellular, transmembrane and intracellular domains. The signal peptide (SP) is not present in mature protein. The extracellular domain contains a sema homology region (Sema) organized in 7 blades; a cysteine-rich region (Psi); and four immunoglobulin-like repeats (Ig-like). The intracellular domain contains juxtamembrane (JM), tyrosine kinase (TK) and carboxyl terminal (CT) domains. Within the TK domain are the ATP binding site (orange), catalytic loop (cat, yellow), activation loop (act, red) and p+1 loop (p+1, green). B. At least three routes of pathway intervention have been followed as selective Met anticancer drug development strategies: 1) fully human monoclonal antibodies that neutralize HGF by binding to one of its two Met binding sites; 2) monovalent (one-armed), monoclonal antibodies designed to bind to Met and inhibit HGF binding; and 3) tyrosine kinase inhibitors classified as type I, type II (TKI_1,2) and type III (TKI₃) as described in text.