MET Inhibitors in Cancer Therapy
http://www.onclive.com/publicati ... s-in-Cancer-Therapy
Abstract
The MET signaling pathway is abnormal in a wide variety of cancers and stimulates cell growth, invasion, and metastasis, as well as promoting resistance to apoptosis. Because of its ubiquitous role in cancer cells, the MET axis has been seen as an attractive target for cancer therapy. Over the last four years, more than 10 anticancer agents targeting different aspects of MET signaling via different mechanisms have been introduced into the clinic. The majority of MET inhibitors are still in late phase I and phase II trials, but at least three compounds, tivantinib, onartuzumab, and cabozantinib, are in phase III trials in lung cancer and medullary thyroid cancer. Ongoing research is aimed at identifying predictive biomarkers that can help identify patients most likely to respond to these compounds. The terminology for this pathway can be confusing. The gene is c-MET, the protein product of the gene is MET.
The MET Signaling Pathway
c-MET was cloned in 1984 and described as a new transforming gene distinct from the then-known RAS family of oncogenes.1 Shortly after c-MET’s initial discovery, its unique high-affinity ligand known as HGF (hepatocyte growth factor, also called scatter factor [SF]), was purified2 and cloned.3 It should be noted that MET is the only known receptor for HGF. The regulatory pathway of MET and HGF governs various cell processes by modulating important signaling cascades in cancer and in normal cells. For example, MET plays a central role in tissue and organ development of embryos, including development of the placenta, liver, and muscle, and the nervous system.4,5 The role of MET in adults is largely restricted to participation in organ regeneration, notably in wound healing, as well as in the pathogenesis of liver, kidney, and heart diseases.6-9
Activation of the MET receptor, usually upon binding of HGF, results in the classic sequence described for receptor tyrosine kinases, including receptor dimerization, phosphorylation of intracellular residues, and initiation of a signal transduction cascade through direct interactions with adaptor proteins, especially GRB2-associated-binding protein 1(GAB1)10, leading to various cellular effects. In addition, the MET pathway interacts with several other cell surface receptors and intracellular pathways, including the HER family (HER1/2/3)11, IGF-1 receptor12, integrins13, and Fas death receptor.14
The Role of the MET Pathway in Cancer
In experimental cancer models, increased signaling through the MET pathway results in acquisition or reinforcement of all elements of the malignant phenotype. These include tumor cell proliferation, motility, invasiveness, migration, and survival. In addition, endothelial cell proliferation and motility occur, resulting in tumor angiogenesis.15 It should also be noted that MET is expressed not only in tumor cells and endothelial cells, but also in osteoblasts (bone-forming cells) and osteoclasts (bone-removing cells). HGF binds to MET on all of these cell types, giving the MET pathway an important role in multiple autocrine and paracrine loops. Activation of MET in tumor cells appears to be important in the establishment of metastatic bone lesions. At the same time, activation of the MET pathway in osteoblasts and osteoclasts may lead to pathological features of bone metastases, including abnormal bone growth (ie, blastic lesions) or destruction (ie, lytic lesions). Thus, targeting the MET pathway may be a viable strategy in preventing the establishment and progression of metastatic bone lesions.
The MET pathway is abnormally regulated in a wide range of human cancers, including the most common epithelial cancers such as breast, colorectal, lung, pancreatic, hepatic, and ovarian cancers.16 Aberrant MET signaling results from several molecular mechanisms, including germline or somatic c-MET gene mutation, c-MET chromosomal rearrangement, c-MET amplification, c-MET transcriptional upregulation, or ligand-dependent autocrine or paracrine changes. These mechanisms are described briefly following.
Receptor and Ligand Overexpression
Transcriptional upregulation of c-MET resulting in MET overexpression is the predominant mechanism of c-MET activation encountered in cancer and is present in different types of cancer, including sarcoma, hematologic malignancies, glioblastoma, medulloblastoma, mesothelioma, melanoma, and in the majority of, if not all, carcinomas.16 In this setting, MET activation depends on ligand binding, following an autocrine, or, probably more frequently, paracrine secretion of HGF.
The molecular mechanisms resulting in MET overexpression remain poorly described. In a minority of cases, gene amplification (described below), may be the basis of high MET expression. In several clinical studies, aberrant MET signaling—in particular, overexpression of MET and/or HGF—has been correlated with poor clinical outcome, exemplified by rapid dissemination of disease and short survival. Overexpression of MET and HGF are also thought to result in resistance of tumor cells to chemotherapy and radiotherapy.16
Gene Amplification
Gene amplification refers to the production of multiple copies of a particular gene, which typically amplifies the function attributed to the gene. To evaluate gene copy number, fluorescence in situ hybridization (FISH) and real-time polymerase chain reaction (PCR) are most frequently used, with Southern blot, chromogenic in situ hybridization (CISH), comparative genomic hybridization (CGH), and single nucleotide polymorphism (SNP) array technologies as alternative tools. When high gene copy number is documented by one of these techniques, a specific reference DNA sequence known not to be amplified in tumor cells must be used in addition, as a denominator, to differentiate amplification from polysomy.
Amplification of oncogenes has been described in many cancers. HER2 amplification in breast cancer, for example, represents the main criterion for selecting patients for trastuzumab therapy. Other examples are EGFR amplification in non-small cell lung cancer (NSCLC) and glioblastoma. Gene amplification is one of the mechanisms resulting in gene copy number increase, which is restricted to a specific section of DNA. Polysomy, in which a specific chromosome is represented more than twice (also known as aneuploidy), is another genetic alteration resulting in multiple copies per cell of the same gene. Polysomy is therefore a biologically different phenomenon from gene amplification.
Gene Mutations
Rarely, the c-MET gene can be affected by somatic or germline point mutations. Sporadic c-MET mutations occurring in the kinase domain have been described to date in ovarian17, head and neck18, childhood liver19, thyroid cancers20, diffuse large B-cell lymphoma21, and gliomas.17-21 In addition, mutations occurring in the juxta-membrane domain of the MET receptor have been demonstrated in gastric, papillary renal cell, mesothelioma22, NSCLC23, small cell lung cancer (SCLC)24, diffuse large B-cell lymphoma21, and melanoma.25 In general, these mutations are rare, typically occurring in 5% or less of these tumors. One exception is in hereditary papillary renal cell carcinoma (RCC), which seems to depend on aberrant MET activity. In this disease, a nonrandom duplication of the allele bearing the mutated MET gene has been described related to trisomy of chromosome 7 in almost all cases.26 Experimental data confirm that these are classic activating mutations.27
HGF specific binding to MET can be prevented by competitors that prevent HGF ligand from interacting with the MET receptor, blocking downstream activation of the pathway. Several anti-HGF humanized antibodies are being studied (rilotumumab, ficlatuzumab).
MET receptor activation can be prevented by receptor blockage by specific monoclonal antibodies that bind to and degrade the receptor (eg, onartuzumab).
MET receptor activation can also be targeted by selective MET kinase inhibitors such as tivantinib (ARQ197) and PF04217903, which have specific selectivity for MET receptor tyrosine kinase, or nonselective MET kinase inhibitors such as crizotinib (PF02341066), cabozantinib (XL184), and foretinib, which have broad activity against MET and other receptor tyrosine kinases that have also been shown to be important in cancer
Anti-HGF Monoclonal Antibodies
A number of monoclonal antibodies that bind HGF are currently in clinical trials. These include ficlatuzumab, rilotumumab, and TAK701.
Ficlatuzumab (previously called AV299) is a humanized anti-HGF IgG1 monoclonal antibody that has completed phase I trials as a single agent and in combination with gefitinib. Toxicities are fatigue, peripheral edema, diarrhea, headache, and hematologic toxicity. Phase II trials are ongoing in NSCLC.28
TAK701 is a humanized IgG1 monoclonal antibody that has just completed phase I testing. Toxicities included fatigue, pleural effusion, and abdominal pain. The future development plans of this compound are unclear.28
Rilotumumab (previously called AMG102) is a fully humanized IgG2 monoclonal antibody29 that has undergone phase I and II clinical trials. It is currently under evaluation as monotherapy in phase IB-II trials in ovarian and renal cancer, as well as in combination with antiangiogenic targeted agents in glioma, erlotinib in NSCLC, panitumumab in colorectal cancer, and platinum-based chemotherapy in SCLC, mesothelioma, and gastric cancer, as well as with mitoxantrone in prostate cancer.
Anti-MET Receptor Antibodies
Onartuzumab (previously called OA-5D5 or OAM4558g and later, METMAb): Earlier efforts to develop MET-directed antibodies failed due to the tendency of bivalent antibodies to cause receptor dimerization, and therefore activate the MET receptor. This agonistic activity has been prevented by producing a monovalent human IgG1 antibody with murine variable domains. The resulting monoclonal antibody, onartuzumab, has been studied in a number of clinical trials. A randomized phase II trial comparing onartuzumab/erlotinib to erlotinib treatment in second- or third-line NSCLC has been reported.30 In the intent-to-treat population of approximately 120 patients, there was no evidence of efficacy in adding onartuzumab to erlotinib. Using a prototype immunohistochemistry (IHC) assay to divide patients in the study into two groups according to a prespecified diagnostic cutoff, there were significant improvements in progression-free and overall survival in the patients with high MET expression by IHC. This “MET high” group was defined as 50% or greater of cells on the diagnostic slide with a staining intensity of 2+ or 3+ (Figure 2). Fifty-four percent of patients were in this “MET high” group. A puzzling finding was the fact that the “low MET” patients did worse when they received onartuzumab in combination with erlotinib. The reasons for this finding are unclear. A phase III trial now under way is using this assay to prospectively enroll patients. Thus, with the help of a novel diagnostic assay, a drug that appeared to be negative in the initial analysis was shown to be potentially active and worthy of further study. Unfortunately, the design of the phase III study will not help confirm or refute the suggestion that “low MET” patients appear to be harmed by a combination of onartuzumab and erlotinib. The benefit from onartuzumab did not seem to be driven by EGFR mutation or FISH status, nor by imbalances in the randomized patient populations.30Onartuzumab is also now under clinical evaluation in randomized, double-blind phase II trials in combination with paclitaxel and bevacizumab in triple-negative breast cancer and in combination with FOLFOX and bevacizumab in colorectal carcinoma.
Receptor Tyrosine Kinase Inhibitors (TKIs)
Various small-molecule inhibitors of the MET receptor tyrosine kinase have been evaluated in the preclinical setting and several have reached the clinic. Some inhibitors are selective, with no other known targets at achievable concentrations in humans, while others inhibit a panel of kinases.
Selective MET TKIs
There are a number of selective MET TKIs in the clinic, including EMD 121406, EMD 1204831, INCB028060, and tivantinib.28
Tivantinib (previously called ARQ197): Tivantinib is probably the most advanced oral MET inhibitor under clinical evaluation. Unlike most other TKIs, tivantinib does not compete for ATP binding and hydrolysis, but blocks the MET receptor in its nonphosphorylated, inactive conformation via an as yet undisclosed mechanism.31
Tivantinib was well tolerated in phase I trials, and pharmacodynamic activity, including reduced total MET and MET phosphorylation, was demonstrated in tumor biopsies from 15 of 51 patients. Common toxicities were fatigue, nausea and vomiting, mucositis, palmar-plantar erythrodysesthesia, hypokalemia, and febrile neutropenia.32
A randomized, placebo-controlled, double-blind phase II clinical trial evaluating the combination of erlotinib/tivantinib compared with erlotinib/placebo in second- and third-line NSCLC has recently been published.33 Progression-free survival, the primary endpoint, was similar in both arms. However, a preplanned exploratory survival analysis demonstrated a trend toward benefit from erlotinib/tivantinib in both PFS and OS in nonsquamous histology, as well as in EGFR wild-type NSCLC patients. Interestingly, in the 15 patients with KRAS mutations, there was also significant benefit in PFS and OS, with poor outcomes reported for KRAS-mutated patients in the erlotinib/placebo arm. There was a trend toward benefit in patients with MET-amplified tumors, with the benefit growing in magnitude with increasing copy number in the erlotinib/tivantinib arm. Consistent with the role of MET in metastases, there was a trend toward delayed development of metastases in patients who received erlotinib in combination with tivantinib.
Based on these results, a phase III randomized trial comparing erlotinib/tivantinib with erlotinib/placebo in nonsquamous NSCLC was activated and has completed accrual.
Non-Selective c-MET TKIs
A number of non-selective MET inhibitors are in clinical testing (Table 2). These include crizotinib, which has been developed and marketed as an ALK inhibitor and is now being evaluated for its MET inhibitory activity; foretinib; and cabozantinib. The agent most advanced in its development as a multitargeted MET inhibitor is cabozantinib.
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