Functional Analysis of c-Met/Hepatocyte Growth Factor Pathway in Malignant Pleural Mesothelioma

Jagadeeswaran, Ramasamy; Patrick, C.; Seiwert, Tanguy Y.; Jagadeeswaran, Sujatha; Zumba, Osvaldo; Nallasura, Vidya; Ahmed, Salman; Filiberti, Rosangela; Paganuzzi, Michela; Puntoni, Riccardo; Kratzke, Robert A.; Gordon, Gavin J.; Sugarbaker, David J.; Bueno, Raphael; Janamanchi, Varalakshmi; Bindokas, Vytas P.; Kindler, Hedy L.; Salgia, Ravi

doi:10.1158/0008-5472.can-04-4567

Cited by 178 publications

(176 citation statements)

References 33 publications

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“…We have previously shown that c-MET/HGF pathway is functional and c-MET is often mutated in SCLC (Ma et al, 2003a). Our recent studies also show that c-MET is mutated in non-SCLC (NSCLC; Ma et al, 2005) and mesothelioma (Jagadeeswaran et al, 2006). Further studies of the role of c-MET/HGF signalling in SCLC will help to improve the understanding of the mechanism of invasion and metastasis in this aggressive disease.…”

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confidence: 76%

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

et al. 2007

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The c-MET receptor can be overexpressed, amplified, or mutated in solid tumours including small cell lung cancer (SCLC). In c-MET-overexpressing SCLC cell line NCI-H69, hepatocyte growth factor (HGF) dramatically induced c-MET phosphorylation at phosphoepitopes pY1230/1234/1235 (catalytic tyrosine kinase), pY1003 (juxtamembrane), and also of paxillin at pY31 (CRKL-binding site). We utilised a global proteomics phosphoantibody array approach to identify further c-MET/HGF signal transduction intermediates in SCLC. Strong HGF induction of specific phosphorylation sites in phosphoproteins involved in c-MET/HGF signal transduction was detected, namely adducin- α [S724], adducin- γ [S662], CREB [S133], ERK1 [T185/Y187], ERK1/2 [T202/Y204], ERK2 [T185/Y187], MAPKK (MEK) 1/2 [S221/S225], MAPKK (MEK) 3/6 [S189/S207], RB [S612], RB1 [S780], JNK [T183/Y185], STAT3 [S727], focal adhesion kinase (FAK) [Y576/S722/S910], p38 α -MAPK [T180/Y182], and AKT1[S473] and [T308]. Conversely, inhibition of phosphorylation by HGF in protein kinase C (PKC), protein kinase R (PKR), and also CDK1 was identified. Phosphoantibody-based immunohistochemical analysis of SCLC tumour tissue and microarray established the role of c-MET in SCLC biology. This supports a role of c-MET activation in tumour invasive front in the tumour progression and invasion involving FAK and AKT downstream. The c-MET serves as an attractive therapeutic target in SCLC, as shown through small interfering RNA (siRNA) and selective prototype c-MET inhibitor SU11274, inhibiting the phosphorylation of c-MET itself and its downstream molecules such as AKT, S6 kinase, and ERK1/2. Investigation of mechanisms of invasion and, ultimately, metastasis in SCLC would be very useful with these signal transduction molecules.

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confidence: 76%

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

et al. 2007

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“…This activates several signaling cascades including the RAS-ERK, PI3 kinase-AKT, or PLC gamma-PKC, which regulate physiological processes including proliferation, migration, and survival. Over-expression, amplification, and mutation in Met have been described in MPM cell lines and inhibition of MET reduces proliferation of MPM cells in vitro (99). However, there currently are no studies, to our knowledge, evaluating efficacy of MET inhibitors in MPM.…”

Section: Met/hgf Inhibitorsmentioning

confidence: 99%

Novel systemic therapy against malignant pleural mesothelioma

Mancuso

Neal

2017

Transl. Lung Cancer Res.

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Malignant pleural mesothelioma is an aggressive tumor of the pleura with an overall poor prognosis. Even with surgical resection, for which only a subset of patients are eligible, long term disease free survival is rare. Standard first-line systemic treatment consists of a platinum analog, an anti-metabolite, and sometimes anti-angiogenic therapy, but there is currently no well-established standard therapy for refractory or relapsed disease. This review focuses on efforts to develop improved systemic therapy for the treatment of malignant pleural mesothelioma (MPM) including cytotoxic systemic therapy, a variety of tyrosine kinase inhibitors and their downstream effector pathways, pharmacologic targeting of the epigenome, novel approaches to target proteins expressed on mesothelioma cells (such as mesothelin), arginine depletion therapy, and the emerging role of immunotherapy. Overall, these studies demonstrate the challenges of improving systemic therapy for MPM and highlight the need to develop therapeutic strategies to control this disease.

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“…PHA-665752, a specific small-molecular inhibitor of MET, caused mesothelioma cell cycle arrest and inhibited phosphorylation of MET, p70S6K, AKT and MAPK (Mukohara et al, 2005). Furthermore, MET small interfering RNA also inhibited mesothelioma cell line proliferation (Jagadeeswaran et al, 2006). VEGF (vascular endothelial growth factor) and VEGFtype C have roles in angiogenesis and lymphangiogenesis in mesothelioma (Ohta et al, 1999;Catalano et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

AXL regulates mesothelioma proliferation and invasiveness

et al. 2010

Oncogene

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Mesothelioma is an asbestos-associated and notoriously chemotherapy-resistant neoplasm. Activation of the receptor tyrosine kinases (RTKs), epidermal growth factor receptor and MET, has been described in subsets of mesothelioma, suggesting that TKs might represent therapeutic targets in this highly lethal disease. We employed proteomic screening by phosphotyrosine immunoaffinity purification and tandem mass spectrometry to characterize RTK activation in mesothelioma cell lines. These assays demonstrated expression and activation of the AXL protein, which is an RTK with known oncogenic properties in non-mesothelial cancer types. AXL was expressed and activated strongly in 8 of 9 mesothelioma cell lines and 6 of 12 mesothelioma biopsies, including each of 12 mesotheliomas with spindle-cell histology. Somatic AXL mutations were not found, but all mesotheliomas expressed an alternatively spliced AXL transcript with in-frame deletion of exon 10, and six of seven mesothelioma cell lines expressed the AXL ligand, growth arrest-specific 6 (GAS6). GAS6 expression appeared to be functionally relevant, as indicated by modulation of AXL tyrosine phosphorylation by knockdown of endogeneous GAS6, and by administration of exogenous GAS6. AXL silencing by lentivirus-mediated short hairpin RNA suppressed mesothelioma migration and cellular proliferation due to G1 arrest. The AXL inhibitor DP-3975 inhibited cell migration and proliferation in mesotheliomas with strong AXL activation. DP-3975 response in these tumors was characterized by inhibition of PI3-K/AKT/mTOR and RAF/MAPK signaling. AXL inhibition suppressed mesothelioma anchorage-independent growth, with reduction in colony numbers and size. These studies suggest that AXL inhibitors warrant clinical evaluation in mesothelioma.

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Functional Analysis of c-Met/Hepatocyte Growth Factor Pathway in Malignant Pleural Mesothelioma

Abstract: c-Met receptor tyrosine kinase (RTK) has not been extensively studied in malignant pleural mesothelioma

Cited by 178 publications

References 33 publications

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

Downstream signalling and specific inhibition of c-MET/HGF pathway in small cell lung cancer: implications for tumour invasion

Novel systemic therapy against malignant pleural mesothelioma

AXL regulates mesothelioma proliferation and invasiveness

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