Mini-reviewc-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention
Introduction
Receptor tyrosine kinases (RTKs) regulate many key processes in mammalian development, cell function, and tissue homeostasis. These diverse processes include cell growth and survival, organ morphogenesis, neovascularization, and tissue repair and regeneration, among others. Dysregulation of RTKs by mutation, gene rearrangement, gene amplification, and overexpression of both receptor and ligand have been implicated as causative factors in the development and progression of numerous human cancers. The validity of these targeted therapies is illustrated by the successes of imatinib targeting Bcr-Abl in chronic myelogenous leukemia and mutant c-Kit in gastrointestinal stromal tumors, trastuzumab in HER-2 overexpressing breast cancers, bevacizumab in colorectal carcinoma, and gefitinib in select non-small cell lung cancers [1].
c-Met is the prototypic member of a sub-family of RTKs which also includes RON. The c-Met RTK family is structurally distinct from other RTK families and is the only known high-affinity receptor for hepatocyte growth factor (HGF), also known as scatter factor (SF) [2], [3]. c-Met and HGF are widely expressed in a variety of tissues, and their expression is normally confined to cells of epithelial and mesenchymal origin, respectively [4], [5]. c-Met and HGF are each required for normal mammalian development and abnormalities associated with both Met- and HGF-null-mice are consistent with proximity of embryonic expression and epithelial–mesenchymal transition defects during organ morphogenesis [6], [7], [8]. Consistent with this finding, the transduction of signaling and subsequent biologic effects of HGF by c-Met has been shown to be important in epithelial–mesenchymal interaction and regulation of cell migration, invasion, cell proliferation and survival, angiogenesis, morphogenic differentiation, and organization of three-dimensional (3D) tubular structures (e.g. renal tubular cells, gland formation, etc.) during development and tissue repair [9], [10]. The specific consequence of c-Met signaling in a given cell (e.g. mitogenesis vs. morphogenesis) is dependent upon the cell type as well as the culture conditions of the experiment.
At a molecular level, binding of activated HGF to the c-Met extracellular ligand-binding domain results in receptor multimerization and phosphorylation of multiple tyrosine residues at the intracellular region. Tyrosine phosphorylation at the c-Met juxtamembrane, catalytic, and cytoplasmic tail domains regulate the internalization, catalytic activity, and docking of regulatory substrates, respectively [11], [12], [13], [14]. Activation of c-Met results in the binding and phosphorylation of adaptor proteins such as Gab-1, Grb2, Shc, and c-Cbl and subsequent activation of signal transducers such as PI-3-Kinase, PLC-γ, STATs, ERK 1 and 2, and FAK [15]. Although other RTKs signal through these pathways, c-Met-dependent signaling is distinct from other RTKs due to: (1) the presence of a unique multi-substrate docking site at the C-terminal region of the receptor; and (2) signaling through an adaptor protein unique to c-Met, called Gab-1, that has been demonstrated to mediate most biologically relevant Met-dependent signals [13], [16], [17]. The time dependence of signaling and spatial regulation of the c-Met signaling complex are distinct from other RTKs and have been proposed as key elements in distinguishing c-Met signaling and biologic function from other RTKs. An additional unique facet of c-Met signaling relative to other RTKs is its reported interaction with focal adhesion complexes and non-kinase binding partners such as β4 integrins, CD44, and semaphorins, which may further add to the complexity of regulation of cell function by this receptor [18], [19], [20].
The roles of docking proteins and signaling mediators in the regulation of diverse c-Met-dependent cell functions have been elucidated in studies using genetic, biological, and pharmacological means of selective modulation of these pathways. First, the involvement of the docking adaptor protein, Gab-1, has been shown to be required in the majority of c-Met-dependent biologic functions including mitogenesis, motility, and morphogenesis [15], [21]. Direct recruitment to a specific binding site at the C-terminal tail of the receptor resulting in sustained activity of Gab-1 has been demonstrated as unique to c-Met compared to other RTKs such as EGFR [22]. This Gab-1 interaction with c-Met has also been demonstrated to play a critical role in sustained signaling through other key adaptor and key signaling proteins [15], [21]. Downstream of Gab-1, the regulation of cell motility, cell disassociation, cell adhesion, and invasion by c-Met was shown to be dependent on both the Erk and PI3K pathways in experiments utilizing specific pharmacologic inhibitors of these pathways [23], [24], [25]. PI3K has also been shown to control cell c-Met-dependent cell survival through the Akt/PKB pathway while signaling through Erk controls mitogenesis suggesting that these two key pathways are critical for most biologic functions of c-Met [26], [27]. In addition to the PI3K and Erk pathways, directional cell migration and invasion were shown to require additional distinct pathways defined by Ras (via Cdc42, Rac1, and Paks), Crk family proteins, and c-src/focal adhesion kinase [28], [29], [30], [31], [32], [33], [34], [35], [36]. The most complex biologic response to HGF activation of c-Met, branching morphogenesis, requires the coordinate, time-dependent regulation of each of these aforementioned signaling pathways in addition to the involvement of STAT3 and PLCγ signaling [37], [38]. These signaling pathways are defined in the context of c-Met inhibition in Fig. 1.
While the controlled regulation of c-Met and HGF have been shown to be important in mammalian development, tissue maintenance, and repair; their dysregulation is implicated in the progression of cancers. Evidence linking c-Met and HGF as causative or progression factors in human cancers include: (1) the overexpression of both receptor and ligand in neoplasms relative to surrounding tissues in numerous indications; (2) the correlation of receptor and ligand overexpression with disease severity and outcome in multiple cancer types; (3) genetic alteration of c-Met by mutation of gene amplification in multiple cancer types; (4) introduction of c-Met and HGF (or mutant c-Met) into cell lines conferred the properties of tumorgenicity and metastatic propensity on engineered cells; (5) introduction of the c-Met or HGF as transgenes into the germline of mice resulted in the appearance of an array of primary and secondary neoplasms; and (6) the inhibition of c-Met or HGF function with dominant-negative receptors, antibody antagonists (both Met and HGF), and biologic antagonists (e.g. NK4) have reversed cancer associated phenotypes such as motility, invasion and proliferation of tumor cells and tumor growth and dissemination in vivo.
Recent reviews have comprehensively covered c-Met and HGF structure, biochemistry, signal transduction, and biologic function [39], [40], [41]. This review attempts to address the utility of targeting c-Met in human cancers, cancers where c-Met inhibition may be particularly effective and therapeutic approaches to targeting the c-Met/HGF pathway. The particular focus on therapeutic approaches will focus on recent data with small-molecule inhibitors of c-Met.
Section snippets
Altered regulation of c-Met
There are a number of mechanisms by which c-Met becomes dysregulated and activated in human cancers. These include overexpression and constitutive kinase activation in the presence and absence of gene amplification, both paracrine and autocrine activation of c-Met by HGF, and mutation of c-Met. c-Met is expressed by most carcinomas and its elevated expression relative to normal tissue has been detected in a number of cancers including lung, breast, colorectal, prostate, pancreatic, head and
Consequences of c-Met and HGF overexpression or mutation of c-Met
The mitogenic, invasive, and motogenic properties of HGF on numerous epithelial cell lines of a diverse array of tissue and tumor origins have been well established and are cell-type-dependent. It is believed that the dysregulation of cell proliferation and survival due to alteration of c-Met signaling may impact the growth of neoplasms while dysregulation of motility and invasion may affect the propensity of a given neoplasm to disseminate. The diverse set of cellular functions regulated by
Approaches to therapeutic inhibition of c-Met in human cancer and consequences of inhibition
Due to the vast information supporting the role of c-Met and HGF in the pathogenesis of human cancers along with successes of other RTK inhibitors, a number of approaches have been attempted to inhibit HGF- or c-Met-dependent signaling. These approaches include: (1) c-Met biologic inhibitors (ribozymes, dominant-negative receptors, decoy receptors, peptides); (2) HGF kringle variant antagonists; (3) HGF antagonist antibodies; (4) c-Met antagonist antibodies; and (5) small-molecule c-Met
Conclusions and future directions
The c-Met RTK is an exciting novel drug target due to the successes observed in clinical studies with other RTK inhibitors, its demonstrated role in experimental oncogenesis, and its dysregulation and correlation with disease prognosis in numerous cancers. The mutation or gene amplification of c-Met in selected clinical populations suggest that certain patients may be exquisitely sensitive to targeted therapy. Furthermore, the broad overexpression of both the ligand and receptor, their role in
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2022, Cellular SignallingCitation Excerpt :Copy number alteration and overexpression of MET gene is found in Korean and Japanese population having PAC [109]. Switch mutation was also detected in codon 545 of exon 9 in Korean and American patients having PAC [104]. Amplification of c-MET gene with consequent protein overexpression and constitutive kinase activity in human tumors is found in gastric, biliary tract, pancreatic, oesophageal carcinomas, liver metastases from colon carcinoma [104].