Targeting the HGF/Met signaling pathway in cancer therapy
- 25 April 2012
- journal article
- review article
- Published by Taylor & Francis Ltd in Emerging Therapeutic Targets
- Vol. 16 (6), 553-572
- https://doi.org/10.1517/14728222.2012.680957
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.Keywords
This publication has 91 references indexed in Scilit:
- Discovery of a Novel Mode of Protein Kinase Inhibition Characterized by the Mechanism of Inhibition of Human Mesenchymal-epithelial Transition Factor (c-Met) Protein Autophosphorylation by ARQ 197Published by Elsevier BV ,2011
- Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR InhibitorsScience Translational Medicine, 2011
- A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastomaNeuro-Oncology, 2011
- MET Pathway as a Therapeutic TargetJournal of Thoracic Oncology, 2009
- Directed Discovery of Agents Targeting the Met Tyrosine Kinase Domain by Virtual ScreeningJournal of Medicinal Chemistry, 2009
- A High Affinity Hepatocyte Growth Factor-binding Site in the Immunoglobulin-like Region of MetPublished by Elsevier BV ,2008
- MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 SignalingScience, 2007
- The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4DNature Structural & Molecular Biology, 2003
- Structure of the Semaphorin-3A Receptor Binding ModuleNeuron, 2003
- Scatter factor is a fibroblast-derived modulator of epithelial cell mobilityNature, 1987