Targeting the HGF/Met signalling pathway in cancer

Abstract

Under normal conditions, hepatocyte growth factor (HGF)-induced Met tyrosine kinase (TK) activation is tightly regulated by paracrine ligand delivery, ligand activation at the target cell surface, and ligand activated receptor internalisation and degradation. Despite these controls, HGF/Met signalling contributes to oncogenesis and tumour progression in several cancers and promotes aggressive cellular invasiveness that is strongly linked to tumour metastasis. The prevalence of HGF/Met pathway activation in human malignancies has driven rapid growth in cancer drug development programmes. Pathway inhibitors can be divided broadly into biologicals and low molecular weight synthetic TK inhibitors; of these, the latter now outnumber all other inhibitor types. We review here the basic properties of HGF/Met pathway antagonists now in preclinical and clinical development as well as the latest clinical trial results. The main challenges facing the effective use of HGF/Met-targeted antagonists for cancer treatment include 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 signalling will continue to be invaluable in meeting these challenges and moving expeditiously toward more effective disease control.

Figure 1. Methods of Blocking the HGF/Met Signaling Pathway

Oncogenic signaling by cellular Met (in blue) and its natural ligands (in yellow) can be antagonized by several distinct inhibitor types (in violet). The intracellular tyrosine kinase (TK) domain and carboxyl terminal docking sites (Y1349 and Y1356) of Met are noted. Pathway inhibitors can be divided broadly into two subtypes (1) biological antagonists of HGF activation and HGF/Met binding, and (2) Met TK inhibitors (TKIs). Biological agents acting outside of the target cell (1) include anti-HGF and anti-Met mAbs, soluble Met ectodomain constructs and truncated HGF isoforms (all of which interfere with HGF/Met binding) and uncleavable forms of HGF (which competitively displace pro-HGF from its activators). Agents acting within the cell (2) include TKIs that competitively displace ATP from its TK domain binding site (TKI-1) and those which bind outside of the ATP binding pocket and inhibit Met TK activation allosterically (TKI-2).