New DrugsThe emerging role of MET/HGF inhibitors in oncology
Introduction
The N-methyl-N′-nitroso-guanidine human osteosarcoma transforming gene (MET) tyrosine kinase is the cell-surface receptor for hepatocyte growth factor (HGF, also known as scatter factor) that is involved in regulating cell proliferation, apoptosis, and migration.[1], [2], [3], [4] MET activity is normally detected in defined stages of embryogenesis and organogenesis.[5], [6], [7], [8], [9] In adults, MET appears to play a role in wound healing and response to organ damage.[10], [11], [12], [13] The MET pathway is also activated in degenerative diseases, including renal and lung fibrosis and cirrhosis.[14], [15], [16]
MET kinase activation results in activation of downstream signaling intermediates such as mitogen-activated protein kinase (MAPK), mammalian target of rapamycin pathway, and signal transducer and activator of transcription pathway.[2], [3], [17], [18] Signals generated from these assembled structures lead to changes in gene expression and cell behavior, with increased proliferation, survival, motility, invasiveness, and stimulation of angiogenesis.19
The MET pathway also engages in crosstalk with the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor (HER) and KRAS signaling pathways, which are critical in the molecular pathogenesis of certain types of cancer, including non-small lung cancer (NSCLC) with intrinsic or acquired resistance to EGFR inhibitors.20
Aberrant MET expression is widely observed in solid and hematologic malignancies.21 Cellular deregulation of MET can occur through mechanisms including MET-receptor overexpression, genomic amplification, mutation, or alternative splicing.[2], [3], [22] These disruptions in normal MET signaling lead to dysregulation of the MET pathway via autocrine, paracrine, or endocrine feedback signaling cascades, inducing disruption of intercellular contacts, promoting cell migration, inhibiting detachment-mediated apoptosis, and resulting in colonization and proliferation of cells at remote sites.[3], [18], [23]
MET was originally identified as the protein product of the translocated promoter region (TPR)-MET transforming oncogene, which was derived from an osteosarcoma cell line.24 The oncogenic TPR-MET fusion protein was demonstrated to have constitutive enzymatic activity that led to development of spontaneous mammary hyperplasia and tumors.25 In other preclinical models, TPR-MET transduction via lentiviral vectors in the livers of adult mice led to slowly progressing hepatocarcinogenesis.26 In humans, TPR-MET chromosomal rearrangement has been detected in gastric cancer tumor tissue.27
Section snippets
Search strategy and selection criteria
References for this review were identified through searches of PubMed with the search terms “MET inhibitor” and “c-met inhibitor.” Additional references were obtained from the reference sections of articles identified using these search terms. In addition, abstracts from annual meetings of the American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), and American Association for Cancer Research (AACR) were searched to identify recent presentations related to
Role of met in tumor biology
MET amplification has been reported in a number of human primary tumors, including gastric and esophageal cancer, medulloblastoma, and NSCLC with acquired resistance to EGFR inhibitors (Table 1).[2], [21], [28] In animal models, conditional MET overexpression in hepatocytes results in development of hepatocellular carcinoma (HCC) that regresses when the transfected gene is inactivated.29 In patients with colorectal cancer (CRC), MET amplification was reported in a higher percentage of liver
Resistance to met inhibitors
As the clinical development of MET inhibitors progresses, experience with tyrosine kinase inhibitors (TKIs) that target other RTKs suggests that patients with tumors that initially respond to MET inhibitors may eventually develop resistance. Acquired resistance of NSCLC to EGFR inhibitors via MET amplification has been demonstrated experimentally and clinically; however, less is known about mechanisms of resistance to MET inhibitors. In a recent study using a MET-dependent gastric cancer cell
Met and lung cancer
In tumor microarray analysis of human cancers, MET and HGF were most commonly expressed in lung tumors (72%).72 Analysis of tyrosine kinase signaling in NSCLC cell lines and tumor samples also demonstrated that MET is the most highly phosphorylated RTK in NSCLC tumor samples, providing additional evidence of the key role of MET in NSCLC.[72], [73]
MET amplification is a rare event in lung cancer, occurring in 4–21% of patients with NSCLC and up to 4% of patients with adenocarcinoma, and is
Clinical development of met inhibitors
Increased understanding of the structure–function relationship of MET and HGF has led to development of several MET and HGF inhibitors. Major classes of MET/HGF inhibitors include monoclonal antibodies (mAbs) that bind HGF or compete with HGF for binding to MET and selective and nonselective MET TKIs (Table 2, Table 3). MET inhibitors are under investigation both as monotherapy or combined with other targeted agents or chemotherapy for the treatment of a wide variety of tumors. Specific tumor
Discussion
The MET pathway has emerged to play a central role in human cancer. Aberrant MET/HGF expression is observed in numerous types of cancer and is associated with a poor prognosis. A more focused understanding of the role of the MET pathway in tumor biology has provided the rationale for clinical development of targeted inhibitors of MET in a variety of tumor types. The MET inhibitors that have progressed furthest in clinical development are all being investigated in patients with NSCLC, although
Conflicts of interest statement
G.V.S. has received honoraria from Eli Lilly, AstraZeneca, Roche, and Pfizer; S.N. has no conflicts of interest to disclose; J.v.P. has served as a consultant for Daiichi Sankyo.
Role of the funding source
Financial support for medical editorial assistance was provided by Daiichi Sankyo, Inc.
Acknowledgments
We thank Bret Wing, PhD, of Accuverus, for his medical editorial assistance with this manuscript.
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