A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth <i>In vivo</i>

Martens, Tobias; Schmidt, Nils-Ole; Eckerich, Carmen; Fillbrandt, Regina; Merchant, Mark; Schwall, Ralph; Westphal, Manfred; Lamszus, Katrin

doi:10.1158/1078-0432.ccr-05-1418

Cited by 302 publications

(231 citation statements)

References 29 publications

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“…These results confirm a key role of c-Met in GBM progression. 29,[48][49][50][51] The lack of regulation of PY142 b-catenin by a c-Met inhibitor does not allow us to conclude if c-Met is phosphorylating this b-catenin site in GBM cells and rather suggests the involvement of other kinases. The proteolytic processing of c-Met is well described and nuclear c-Met has been linked to invasive cancers.…”

Section: Resultsmentioning

confidence: 95%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glialderived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/b-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that b-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) b-catenin and dephospho S/T b-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsyderived glioma cell cultures. We found that PY142 b-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 b-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active b-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active b-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 b-catenin and Snail/Slug. Importantly, the expression of mutant Y142F b-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 b-catenin as a nuclear b-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.

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Section: Resultsmentioning

confidence: 95%

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

et al. 2015

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“…In particular, a recent phase II clinical trial with MetMAb (onartuzumab, a one-armed antibody designed to compete with HGF by binding the extracellular portion of MET; ref. 73 ), conducted in patients with advanced NSCLC, has shown the clinical effi cacy of the combined therapy. This phase II study showed that patients whose tumors had high MET levels experienced a twofold increase in progression-free survival in response to MetMAb plus erlotinib compared with erlotinib alone.…”

Section: Clinical Translationmentioning

confidence: 99%

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

Corso

Giordano

2013

Cancer Discovery

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Targeted therapies have opened new perspectives in clinical oncology. However, clinicians have observed a lack of response in a relevant percentage of patients and frequent relapse in patients who initially respond. Therefore, a compelling challenge is to identify mechanisms underlying resistance and strategies to circumvent these hurdles. A growing body of evidence indicates that MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is frequently implicated in resistance to targeted therapies. In this review, we highlight cell-autonomous and non-cell-autonomous mechanisms through which MET drives resistance, and we discuss some unsolved issues related to the selection of patients who could benefi t from combined therapies. Signifi cance:Resistance is, at present, the major limitation to the effi cacy of targeted therapies. Inappropriate MET activation is very frequently implicated in the onset of primary and secondary resistance to these therapies. Deciphering the role of the HGF/MET axis in resistance to different drugs could guide the design of new clinical trials based on combinatorial therapies, and it might help to overcome, or possibly prevent, the onset of resistance. Cancer Discov; 3(9);

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“…Xenografts derived from U87MG human glioblastoma cells, which activate MET by an autocrine mechanism (8), and H441 human lung cancer cells, which express phospho-MET (34), are sensitive to multitargeted kinase inhibitors (14,15,34). The growth of U87MG tumors is additionally impeded by ribozymes and antibodies directed at HGF (9,10) or MET (9,12). These data suggest that U87MG tumors depend on MET activity for their growth, but biologic agents targeting receptor tyrosine kinases can act via mechanisms other than inhibition of catalysis.…”

Section: Sgx523 Inhibits Met But Not Other Kinases In Cellsmentioning

confidence: 99%

“…In other malignancies, such as glioblastoma, autocrine activation of MET by HGF has been shown (8), and MET inhibition is effective in mouse models of glioblastoma (9)(10)(11)(12). The wealth of evidence linking MET to cancer has motivated efforts, using various strategies, to inhibit MET signaling (5,(9)(10)(11)(12)(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

Buchanan¹,

Hendle²,

Lee³

et al. 2009

Molecular Cancer Therapeutics

127

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The MET receptor tyrosine kinase has emerged as an important target for the development of novel cancer therapeutics. Activation of MET by mutation or gene amplification has been linked to kidney, gastric, and lung cancers. In other cancers, such as glioblastoma, autocrine activation of MET has been demonstrated. Several classes of ATP-competitive inhibitor have been described, which inhibit MET but also other kinases. Here, we describe SGX523, a novel, ATP-competitive kinase inhibitor remarkable for its exquisite selectivity for MET. SGX523 potently inhibited MET with an IC 50 of 4 nmol/L and is >1,000-fold selective versus the >200-fold selectivity of other protein kinases tested in biochemical assays. Crystallographic study revealed that SGX523 stabilizes MET in a unique inactive conformation that is inaccessible to other protein kinases, suggesting an explanation for the selectivity. SGX523 inhibited MET-mediated signaling, cell proliferation, and cell migration at nanomolar concentrations but had no effect on signaling dependent on other protein kinases, including the closely related RON, even at micromolar concentrations. SGX523 inhibition of MET in vivo was associated with the dose-dependent inhibition of growth of tumor xenografts derived from human glioblastoma and lung and gastric cancers, confirming the dependence of these tumors on MET catalytic activity. Our results show that SGX523 is the most selective inhibitor of MET catalytic activity described to date and is thus a useful tool to investigate the role of MET kinase in cancer without the confounding effects of promiscuous protein kinase inhibition. [Mol Cancer Ther 2009;8(12):3181-90]

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A Novel One-Armed Anti-c-Met Antibody Inhibits Glioblastoma Growth In vivo

Cited by 302 publications

References 29 publications

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo

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