[Frontiers in Bioscience 18, 454-473, January 1, 2013]

Biological significance and targeting of c-Met tyrosine kinase receptor in cancer

Liliane Goetsch1, Veronique Caussanel1, Nathalie Corvaia1

1Centre d'Immunologie Pierre Fabre, 5 avenue Napoleon III F-74164 Saint Julien en Genevois, France

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The c-Met receptor in cancer diseases
3.1. c-met structure
3.2. The c-Met signaling pathways
4. HGF/c-Met axis alterations in cancer diseases
4.1. c-Met over-expression
4.2. Phosphorylation of c-Met
4.3. Mutated c-Met forms
5. Crosstalk between c-Met and other signaling pathways
5.1. Crosstalk between c-Met and EGFR
5.2. Crosstalk between c-Met and Her2
6. Ongoing clinical trials: safety, efficacy and first selected biomarkers
6.1. ARQ 197 Tyrosine kinase inhibitor
6.2. MetMab monovalent antibody targeting c-Met
7. Future perspectives
8. Acknowledgment
9. References

1. ABSTRACT

c-Met is a tyrosine kinase receptor largely described to be involved in cancer progression and metastasis. In such pathologic situation, many alterations of this receptor were noticed that include transcriptional overexpression, gene amplification, somatic or germline mutations and/or ligand dependent autocrine/paracrine loops. More recently it has also been suggested that c-Met would be involved in resistance to targeted therapies directed towards EGFR or angiogenesis. Major efforts from a large number of pharmaceutical companies are invested dedicated to evaluate the efficacy of either small molecule inhibitors or monoclonal antibodies directed against c-Met or its unique ligand HGF. A series of promising results from the first completed clinical trials indicated that compounds targeting c-Met have an acceptable toxicity profile and that efficacy was noticed in some treated patients. Non squamous NSCLC patients that express more often high levels of c-Met seemed to represent a most sensitive subset for and anti-c-Met/erlotinib therapy. Many Phase III trials are currently recruiting and a particular effort was performed in order to discover biomarkers associated with efficacy and patient selection. This review will provide an overview of the current knowledge on the c-Met axis for development of novel therapeutics in Oncology.