Letter to editor

c-Met is a proto-oncogene that encode a protien known as hepatocyte growth factor receptor (HGFR) [1–3]. It is essential for embryonic development, wound healing and organ morphogenesis [4, 5]. MET is a membrane receptor. It stimulates cell scattering, invasion, protection from apoptosis and angiogenesis [6]. MET is normally expressed by cells of epithelial origin [4]. Deregulated activity of c-Met can cause a wide variety of different cancers, such as colorectal, thyroid, renal cell, ovary, breast, pancreas, prostate, liver, and melanoma and in gastric carcinoma [7–11].

Hepatocyte growth factor (HGF) is the only known ligand of the MET receptor [4, 5, 12]. Upon HGF stimulation, MET induces MET kinase catalytic activity which triggers transphosphorylation of the tyrosine Tyr 1234 and Tyr 1235. These two tyrosines engage various signal transducers, thus initiating a whole spectrum of biological activities driven by MET, collectively known as the invasive growth program. Over expression, gene amplification, mutation, a ligand-dependent auto- or paracrine loop or an untimely activation of RTK leads to c-Met dysregulation [4, 13]. Cancer development is closely associated with different oncogenic pathways. RAS pathway mediates scattering and proliferation signals which lead to branch morphogenesis [14]. PICK3 pathways activates either directly or through down stream of RAS pathway [15]. Beta catenin pathway participates in transcriptional regulation of numerous genes while NOTCH pathway activates through Delta ligand [16, 17]. Activation of these oncogenic pathways (RAS, PI3K, STAT3, beta-catenin), angiogenesis and cells dissociation due to metalloprotease production, which often leads to metastasis, are involved in the development of cancer [18].

c-Met inhibitors are relatively new class of small molecules that inhibit the enzymatic activity of the c-Met tyrosine kinase. Pyrrole-indolinone (PHA-665752) is a prototype selective class of inhibitors that inhibits HGF/SF-induced receptor phosphorylation [4, 5, 19]. There are basically two classes of c-Met inhibitors, ATP competitive and ATP non-competitive inhibitor. ATP competitive inhibitors are further divided into two classes; class I (SU-11274-like) and class II (AM7-like) on the basis of different types of binding and a third group of non-competitive ATP inhibitor that binds in a different way to the other two [20, 21]. Class I inhibitors are selective, U-shaped and attached to the activation loop of c-Met. JNJ-38877605 ( for advanced and refractory solid tumors) and PF-04217903 are class I met inhibitors that underwent phase I clinical trials in 2010 [22]. Class II inhibitors have urea group in either cyclic or acyclic form. Foretinib XL880 is a class II met inhibitor that targets multiple tyrosine kinases, primary targets are MET, VEGFR2 and KDR. It has completed phase-2 clinical trial with indications for head and neck, gastric and renal cell carcinoma [22, 23]. Other candidates undergoing trials include Merck’ MK-2461, Bristol Meyers Squib’ BMS-777607, GSK/Exelixis’ GSK/1363089/XL 880 and BMS/Exelixis’ XL-184 [12, 22].

The Met pathway is one of the most frequently dysregulated pathways in human cancer [12]. c-Met inhibitors that are currently in clinical trials include cabozantinib and foretinib. Cabozantinib (XL184) was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer [24]. Patients taking this medication should not ingest grapefruit or grapefruit juice as it may increase the concentration of the drug in the patient's blood [25]. Foretinib is yet an experimental drug candidate for the treatment of cancer [26].

The use of c-Met inhibitors with other therapeutic agents could be crucial for overcoming potential resistance as well as for improving overall clinical benefit. As a key element in the development of any targeted therapy, the biochemical and molecular determination of the precise functions of the Met pathway in the context of other relevant pro-cancer pathways will undoubtedly play a significant role in this effort [12]. More implications are likely to be discovered as new horizons in cancer therapeutics are unveiled [27].