Document Detail


Expression and clinical relevance of MET and ALK in Ewing sarcomas.
MedLine Citation:
PMID:  23335077     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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, post-chemotherapy 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/ALK-inhibitor 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%, resp.). ALK expression was significantly lower in post-chemotherapy resections compared to paired untreated primary tumors (p=0.031, z=-2.310, n=11). In primary tumors (n=20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p=0.014). There was a trend towards a poor event-free survival (EFS) (67 vs. 111 months, p=0.078) and OS (88 vs. 128 months, p=0.074) in patients with highest ALK levels (n=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 μmol/L), NVP-TAE684 (IC(50) 0.15-0.79 μmol/L) and cabozantinib (IC(50) 2.69-8.27 μmol/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.
Authors:
Emmy D G Fleuren; Melissa H S Roeffen; William P Leenders; Uta E Flucke; Myrella Vlenterie; Hendrik W Schreuder; Otto C Boerman; Winette T A van der Graaf; Yvonne M H Versleijen-Jonkers
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-21
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  -     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-21     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2013 UICC.
Affiliation:
Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. E.Fleuren@onco.umcn.nl.
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