The MET Receptor Tyrosine Kinase Is a Potential Novel Therapeutic Target for Head and Neck Squamous Cell Carcinoma

Seiwert, Tanguy Y.; Jagadeeswaran, Ramasamy; Faoro, Leonardo; Janamanchi, Varalakshmi; Nallasura, Vidya; Dinali, Mohamed El; Yala, Soheil; Kanteti, Rajani; Cohen, Ezra E.W.; Lingen, Mark W.; Martin, Lee; Krishnaswamy, Soundararajan; Klein‐Szanto, Andres J.; Christensen, James G.; Vokes, Everett E.; Salgia, Ravi

doi:10.1158/0008-5472.can-08-2881

Cited by 235 publications

(243 citation statements)

References 45 publications

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“…This expression pattern closely resembles data in other cancer types. 5,23,24 Most importantly, in our study, membranous MET expression significantly correlated with a poor OS in ES patients. This suggests a functional role of MET in ES, because only MET receptors at the cell membrane are thought to be involved in (ligand induced) signal transduction.…”

Section: Discussionsupporting

confidence: 54%

“…39 Because crizotinib and cabozantinib already demonstrated marked suppression of angiogenesis in various in vivo carcinoma models, it would be worthwhile to test these inhibitors in in vivo ES models as well. 24,40 There is a compelling need for the introduction of novel therapies in ES, and this study provides for the first time a rationale for MET and/or ALK targeting in ES. Because these targets have been implicated in multiple other cancers, various inhibitors have been and are still being developed.…”

Section: Discussionmentioning

confidence: 97%

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Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALKinhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p 5 0.031, z 5 22.310, n 5 11). In primary tumors (n 5 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p 5 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p 5 0.078) and OS (88 vs. 128 months, p 5 0.074) in patients with highest ALK levels (n 5 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC 50 1.22-3.59 lmol/L), NVP-TAE684 (IC 50 0.15-0.79 lmol/L) and cabozantinib (IC 50 2.69-8.27 lmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.Ewing sarcoma (ES) is the second most common primary malignant bone tumor occurring in children and adolescents. Although multimodal treatment has improved the prognosis of patients with localized ES during the last decades, the final outcome has not improved for patients with metastatic disease and side effects of treatment could be severe. 1,2 This urges the need for novel therapeutic strategies, including targeted therapies directed against molecules involved in the pathogenesis and progression of ES, 3 Although at present some receptor tyrosine kinases (RTKs) have been implicated in ES, predominantly the insulin-like growth factor-1 receptor (IGF-1R), and to a lesser extent also platelet-derived growth factor receptor (PDGFR) and c-KIT, the role of several other receptors remains to be investigated. 4 In this study, we addressed the role of MET and anaplastic lymphoma kinase (ALK) in ES.MET is a RTK known to be deregulated in many cancers. At present, the hepatocyte growth factor (HGF) is the only known ligand for MET. Upon receptor binding, MET undergoes rapid tyrosine phosphorylation and several intracellular signaling cascades are activated, including the phosphatidylinositol 3 (PI3)/Akt kinase and extracellular signal regulated kinase (Erk) pathways. Several studies have shown that HGF/ MET signaling is involved in c...

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 97%

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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“…Finally, coding mutations are rare in HNSCC, but the OPSCC TCGA dataset suggests that there may be a subset of HPV-negative MET over expressed OPSCC that are mutually exclusive of PIK3CA mutations and PDGFA over expression. MET is a recognized drug target in head and neck cancer [60].…”

Section: Discussionmentioning

confidence: 99%

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

Saba

Wilson

Doho

et al. 2014

Head and Neck Pathol

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The role of molecular methods in the diagnosis of head and neck cancer is rapidly evolving and holds great potential for improving outcomes for all patients who suffer from this diverse group of malignancies. However, there is considerable debate as to the best clinical approaches, particularly for Next Generation Sequencing (NGS). The choices of NGS methods such as whole exome, whole genome, whole transcriptomes (RNA-Seq) or multiple gene resequencing panels, each have strengths and weakness based on data quality, the size of the data, the turnaround time for data analysis, and clinical actionability. There have also been a variety of gene expression signatures established from microarray studies that correlate with relapse and response to treatment, but none of these methods have been implemented as standard of care for oropharyngeal squamous cell carcinoma (OPSCC). Because many genomic methodologies are still far from the capabilities of most clinical laboratories, we chose to explore the use of a combination of off the shelf targeted mutation analysis and gene expression analysis methods to complement standard anatomical pathology methods. Specifically, we have used the Ion Torrent AmpliSeq cancer panel in combination with the NanoString nCounter Human Cancer Reference Kit on 8 formalin-fixed paraffin embedded (FFPE) OPSCC tumor specimens, (4) HPVpositive and (4) HPV-negative. Differential expression analysis between HPV-positive and negative groups showed that expression of several genes was highly likely to correlate with HPV status. For example, WNT1, PDGFA and OGG1 were all over-expressed in the positive group. Our results show the utility of these methods with routine FFPE clinical specimens to identify potential therapeutic targets which could be readily applied in a clinical trial setting for clinical laboratories lacking the instrumentation or bioinformatics infrastructure to support comprehensive genomics workflows. To the best of our knowledge, these preliminary experiments are among the earliest to combine both mutational and gene expression profiles using Ion Torrent and NanoString technologies. This reports serves as a proof of principle methodology in OPSCC.Electronic supplementary material The online version of this article

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“…Therapy combining various targeted agents or other standard therapies with MET inhibitors has also been explored in other preclinical studies, including synergistic effects of when MET and EGFR inhibitors were combined in NSCLC cell lines, and head and neck squamous cell carcinoma (SCCHN) cells (24,25). Combined inhibition of MET and mammalian target of rapamycin resulted in cooperative inhibition of cell growth in TPR-MET transformed cells expressing a constitutively active variant of MET, and in MET-expressing NSCLC cells (26).…”

Section: Hfg/met In Lung Cancermentioning

confidence: 99%

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

Salgia

2017

Molecular Cancer Therapeutics

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124

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MET or hepatocyte growth factor (HGF) receptor pathway signaling mediates wound healing and hepatic regeneration, with pivotal roles in embryonic, neuronal, and muscle development. However, dysregulation of MET signaling mediates proliferation, apoptosis, and migration and is implicated in a number of malignancies. In non-small cell lung cancer (NSCLC), aberrant MET signaling can occur through a number of mechanisms that collectively represent a significant proportion of patients. These include MET or HGF protein overexpression, MET gene amplification, MET gene mutation or fusion/rearrangement, or aberrations in downstream signaling or regulatory components. Responses to MET tyrosine kinase inhibitors have been documented in clinical trials in patients with MET-amplified or METoverexpressing NSCLC, and case studies or case series have shown that MET mutation/deletion is a biomarker that is also predictive of response to these agents. However, other recent clinical data have highlighted an urgent need to elucidate optimal biomarkers based on genetic and/or protein diagnostics to correctly identify patients most likely to benefit in ongoing clinical trials of an array of MET-targeted therapies of differing class. The latest advances in the development of MET biomarkers in NSCLC have been reviewed, toward establishing appropriate MET biomarker selection based on a scientific rationale. Mol Cancer Ther; 16(4); 555-65.Ó2017 AACR.

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The MET Receptor Tyrosine Kinase Is a Potential Novel Therapeutic Target for Head and Neck Squamous Cell Carcinoma

Cited by 235 publications

References 45 publications

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Mutation and Transcriptional Profiling of Formalin-Fixed Paraffin Embedded Specimens as Companion Methods to Immunohistochemistry for Determining Therapeutic Targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle

MET in Lung Cancer: Biomarker Selection Based on Scientific Rationale

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