The MET signaling network has emerged as an important target for cancer therapy, with a particularly significant role in controlling the cancer hallmarks of metastasis and angiogenesis.
Figure. c-MET receptor tyrosine kinases (RTKs) activated via hepatocyte growth factor (HGF) binding can result in multiple downstream effects conducive to cancerous cells. This figure illustrates the ways in which activated c-MET RTKs can recruit a variety of proteins such as GRB2, GAB1, PLCγ, SRC, and SHP2, and signal numerous pathways.
Adapted from Liu X, Newton RC, Scherle PA. Developing c-MET pathway inhibitors for cancer therapy: progress and challenges. Trends Mol Med. 2010;16(1); 37-45.
It has been just over a quarter of a century since the discovery of the MET receptor and its ligand, hepatocyte growth factor (HGF). During this time, this signaling network has emerged as an important target for cancer therapy, with a particularly significant role in controlling the cancer hallmarks of metastasis and angiogenesis. Research has yielded a veritable bounty of potential therapies targeting this pathway, many of which are now entering the early stages of clinical trials, with a handful progressing into the later stages of development.
Discovered in the mid-1980s, c-MET is a proto-oncogene (a normal gene that, under certain circumstances, has the potential to become a cancer-causing oncogene). The protein encoded by the c-MET gene is a cell surface receptor known as the mesenchymal epithelial transition factor, or MET receptor.
As with many other cell surface receptors discussed in the “Pathways” series, such as the epidermal growth factor receptor (EGFR), the MET receptor belongs to the receptor tyrosine kinase (RTK) family. This means that upon activation by a ligand, two receptor molecules pair up (dimerization), which activates the tyrosine kinase activity of the receptor and leads to its phosphorylation. The phosphorylated regions of the receptor act as binding sites for a range of signal transduction proproteins. HGF is the only known ligand for the MET receptor, and, as a result, the receptor is also often referred to as the HGF receptor (HGFR).
Among the many important signaling cascades induced by MET receptor activation are the phosphatidylinositol-3-kinase (PI3K)/Akt and the RAS/mitogen-activated protein kinase (MAPK) pathways. Furthermore, there is a substantial amount of cross-talk and interaction between the MET receptor pathway and those of the EGFR, vascular endothelial growth factor receptor (VEGFR), and beta-catenin/Wnt pathways.
The biological responses induced by the MET receptor pathway include cell proliferation and survival. However, MET receptor signaling plays a particularly important role in coordinating cell motility, invasion, and angiogenesis (the formation of new blood vessels), and plays a very active part in the development of the embryo and in the formation of organs during early human development.
In adults, activation of the MET receptor pathway is much more tightly regulated. MET receptor is predominantly expressed on cells of epithelial origin, while its ligand, HGF, is produced predominantly by mesenchymal cells. The MET receptor pathway is typically only switched on in adults in order to coordinate processes such as wound healing and tissue regeneration.
Given its important function in cell motility, invasion, and angiogenesis, it is unsurprising that cancer cells frequently hijack the MET receptor pathway to assist in the development of several hallmark capabilities. Abnormal MET expression is found in many different types of human malignancy, including kidney, liver, stomach, breast, and brain cancers, and it typically correlates with a poor prognosis. Among the multiple mechanisms of aberrant MET pathway activation is overexpression of the MET receptor or its ligand HGF and point mutations within the c-MET gene.
In cancer cells, inappropriate activation of MET receptor signaling leads to a number of different biological outcomes that assist cancer development, which are collectively termed the invasive growth program. As part of this program, MET receptor activation promotes angiogenesis and aids in cancer cell invasion.
Furthermore, HGF is often referred to as scatter factor, since its activation of the MET receptor also enables cells to dissociate from one another and scatter. Finally, MET receptor signaling also drives the epithelial-to-mesenchymal transition (EMT; the conversion of cells from an epithelial phenotype to a more motile mesenchymal phenotype), which is an essential part of the ability of cancer cells to acquire the final hallmark of cancer, the ability to metastasize or spread to distant sites around the body.
For these reasons, both the MET receptor and HGF have emerged as key targets for cancer therapy.
A large number of MET receptor and HGF-targeted therapies are at various stages of clinical development. As of mid-2009, there were more than 70 patent applications for MET-related drugs, and the number has likely increased to well over 100 today.
Thus far, the FDA has not approved any agent on the basis of its ability to inhibit the MET receptor. Crizotinib (Xalkori, Pfizer) is a dual inhibitor of c-MET and anaplastic lymphoma kinase (ALK); it was approved in August for the treatment of patients with late-stage non-small cell lung cancer (NSCLC) who test positive for mutations of the ALK gene.
Several different strategies have been employed with respect to targeting the MET receptor pathway. Since MET is a tyrosine kinase receptor, it is an ideal candidate for the development of small-molecule kinase inhibitors, and indeed the majority of agents in clinical development are tyrosine kinase inhibitors.
Sponsors (Trial Number)
Advanced medullary thyroid cancer (EXAM)
Cabozantinib vs Placebo
Previously treated symptomatic castrationresistant prostate cancer (COMET-2)
Cabozantinib plus placebo mitoxantrone injections and placebo prednisone capsules vs Mitoxantrone plus prednisone and placebo cabozantinib tablets
Nonsquamous, non-small cell lung cancer
Tivantinib plus erlotinib vs Placebo plus erlotinib
Daiichi Sankyo Inc ArQule (NCT01244191)
MET diagnostic-positive non-small cell lung cancer
Onartuzumab plus erlotinib vs Erlotinib plus placebo
* Crizotinib (Xalkori, Pfizer) is under investigation in earlier-phase trials for its c-MET activity and in later trials for its effect on patients with ALK-positive non-small cell lung cancer.
Source: US National Institutes of Health ClinicalTrials.gov website, clinicaltrials.gov
There are several small-molecule inhibitors in clinical trials that are specific to the MET receptor. Furthest along in development is tivantinib (ARQ197, ArQule), currently undergoing phase I, II, and III trials in patients with colorectal cancer, NSCLC, solid tumors, and gastric cancer, among others. INCB28060 (Incyte Corporation/Novartis Pharmaceuticals) and foretinib, formerly known as XL880 (GlaxoSmithKline/ Exelixis), are also in phase I or I/II clinical trials.
In addition to these specific inhibitors, there are a number of inhibitors that are less specific and target MET receptor among multiple other kinases or in combination with one other kinase. For example, there are numerous dual MET and VEGFR inhibitors in development. Furthest along in development in this category are crizotinib, currently undergoing phase I and II trials for numerous different cancer types, as well as phase III trials in ALK-positive patients with NSCLC, and cabozantinib, formerly known as XL184 (Exelixis), in phase I and II trials, and reaching phase III trials for thyroid cancer.
Other nonspecific MET inhibitors under development are AMG 208 (Amgen), MGCD265 (MethylGene Inc), and amuvatinib (Astex Pharmaceuticals, Inc), all undergoing phase I or phase I/II trials. Many more candidates are undergoing preclinical development and will likely be joining these agents in clinical trials in the near future.
A second strategy for targeting the MET receptor/HGF pathway is to use monoclonal antibodies, which bind to either the receptor or the ligand and prevent receptor-ligand interaction, and hence, activation of the pathway.
The HGF monoclonal antibodies currently in clinical development include rilotumumab (AMG 102, Amgen), undergoing phase I and II trials in a number of different cancer types including glioma, ovarian cancer, gastric/esophageal cancer, and NSCLC, both alone and in combination with chemotherapeutic agents. Ficlatuzumab (AV-299, Aveo Pharmaceuticals, Inc) is in phase I/II clinical trials for NSCLC.
The development of antibodies to the MET receptor met a hitch in the early stages of development, when it was discovered that bivalent monoclonal antibodies could actually promote the dimerization and activation of the MET receptor. A number of monovalent monoclonal antibodies are now being developed. Among them, onartuzumab (MetMAb, Genentech) is furthest along, in phase III trials in combination with the EGFR inhibitor erlotinib (Tarceva, Genentech) in patients with NSCLC.
Several other strategies that have been explored include the use of “decoy MET,” a soluble shortened version of the MET receptor, which prevents ligand binding and receptor dimerization. CGEN-241 (Compugen) is currently in preclinical development in this class.
Also under development are uncleavable forms of HGF (immature forms that cannot be cleaved into the mature form, and therefore are unable to activate the MET receptor), and shortened splice variants of HGF, such as NK4, which has demonstrated both HGF antagonistic and antiangiogenic activity in preclinical testing.
The majority of MET pathway-targeted agents are still undergoing clinical testing, but the preliminary results from a number of trials have been made available. They suggest that MET therapeutics show great promise of strong activity and genuine clinical benefit in patients with a range of different malignancies, including advanced or metastatic cancers.
A trial of onartuzumab in combination with erlotinib in patients with NSCLC demonstrated increased progression-free survival (PFS). Similarly, a trial of AMG 102 in combination with chemotherapy in patients with advanced gastric adenocarcinoma demonstrated increased overall survival (OS). Tivantinib in combination with erlotinib increased both OS and PFS in patients with NSCLC, and cabozantinib has shown significant activity against solid tumors (including breast, melanoma, and liver) and metastatic castration-resistant prostate cancer.
The results of these trials highlight two important points relating to MET-targeted therapies. First, in most cases optimal results were observed in patients with high MET expression, and in some cases there was a reduction in PFS in patients with low or no MET expression. This highlights the very real need for patient stratification in these trials, and in identifying those patients who will most benefit from these agents.
The second point that arises from these trials is that the optimal use of METtargeted therapies may come from combination with other targeted therapies, such as erlotinib, or specific agents that target other downstream signaling pathways such as PI3K/Akt, MEK, or STAT inhibitors.
In fact, MET amplification has been reported to be a mechanism by which cancer cells acquire resistance to erlotinib. Therefore, it may prove particularly useful as a combination therapy to prevent the development of resistance.
Jane de Lartigue, PhD, is a freelance medical writer and editor based in the United Kingdom.