MET As a Potential Target for the Treatment of Upper Gastrointestinal Cancers: Characterization of Novel c-Met Inhibitors from Bench to Bedside
A. Avan, M. Maftouh, N. Funel, M. Ghayour-Mobarhan, U. Boggi, G.J. Peters and E. Giovannetti
Affiliation: Department Medical Oncology, VU University Medical Center; Cancer Center Amsterdam, De Boelelaan 1117; 1081 HV Amsterdam, The Netherlands.
The receptor tyrosine kinase mesenchymal-epithelial transition factor (c-Met) plays a pivotal role in regulation
of cell proliferation and migration. Abnormal expression of c-Met has been associated with poor prognosis in several cancer
types, including upper gastrointestinal malignancies. Moreover, c-Met interaction with multiple signalling pathways
involved in tumor growth and invasive/metastatic phenotype has gained substantial attention in the last few years, suggesting
the therapeutic potential of this target. This has led to the development and evaluation of a number of c-Met inhibitors.
Here we describe the critical role of the HGF/c-Met pathway in cancer, as well as the preclinical and clinical investigations
on c-Met inhibitors in solid tumors, with particular emphasis on recent findings with small-molecule inhibitors
in gastrointestinal cancers. Clinical trials with several of these novel inhibitors have been encouraging and one of
them, crizotinib (dual c-Met/ALK inhibitor), has recently been approved for lung cancers with ALK-rearrangement. There
are accumulating evidences on the therapeutic potential of this and other c-Met inhibitors for the treatment of other malignancies,
such as gastric and pancreatic cancers. These inhibitors might be used in combination with chemotherapy as well
as with other biological agents, in order to overcome different resistance mechanisms. However, further studies are
needed to identify determinants of the activity of c-Met inhibitors, through the analysis of genetic and environmental alterations
affecting c-Met and parallel pro-cancer pathways. These studies will be critical to improve the efficacy and selectivity
of current and future anticancer strategies targeting c-Met.
Keywords: Antitumor therapy, cancer aggressive behaviour, clinical development, c-Met inhibitors, HGF, MET, personalized
medicine, preclinical studies, resistance to targeted agents, upper gastrointestinal cancers.
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