The c-Met Inhibitors: A New Class of Drugs in the Battle Against Advanced Nonsmall- Cell Lung Cancer

Assunta      Sgambato; Francesca      Casaluce; Paolo      Maione; Antonio      Rossi; Emanuela      Rossi; Alba      Napolitano; Giovanni      Palazzolo; Maria      Anna Bareschino; Clorinda      Schettino; Paola      Claudia Sacco; Fortunato      Ciardiello; Cesare      Gridelli

doi:10.2174/138161212803582478

Abstract

Lung cancer, of which non-small-cell lung cancer (NSCLC) is the most common form, remains the leading cause of cancerrelated mortality worldwide, with many patients presenting with advanced disease at initial diagnosis. In advanced NSCLC patients whose tumors harbor activating epidermal growth factor receptor (EGFR) mutations, the use of EGFR tyrosine kinase inhibitors (TKIs) as first-line treatment has provided an unusually large progression-free-survival (PFS) benefit, a significantly high response rate (RR) and decreased toxicity when compared with cytotoxic chemotherapy in several phase III randomized trials; however, resistance invariably occurs. There are multiple mechanisms defined by which tumor cells may become independent of EGFR such as the well-characterized example of mesenchymal-epithelial transition factor (MET) amplification. Upon initial diagnosis of NSCLC, MET gene amplification is uncommon; however, acquired MET amplification has been noted in up to 20% of EGFR-mutated tumors that have been pretreated with an EGFR TKI. In tumors containing MET gene amplification, stimulation of the tumor occurs via the co-receptor HER-3 resulting in activation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway, thereby circumventing the effects of an EGFR TKI. Recently, the targeting of the MET pathway has been attempted with small molecules and with monoclonal antibodies. This review will explain the MET signaling pathway and biology in cancer and the recent clinical development and advances of MET/HGF targeting agents in the treatment of advanced NSCLC.

Keywords: c-MET, MET inhibitors, MetMAb, non-small-cell lung cancer, targeted therapy, tivantinib, diagnosis, epidermal growth factor receptor (EGFR), mutations, gene amplification.