FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro.

// Helen Kunstlinger 1 , Jana Fassunke 1 , Hans-Ulrich Schildhaus 2 , Benedikt Brors 3 , Carina Heydt 1 , Michaela Angelika Ihle 1 , Gunhild Mechtersheimer 4 , Eva Wardelmann 5 , Reinhard Buttner 1 and Sabine Merkelbach-Bruse 1 1 Institute of Pathology, University Hospital Cologne, Cologne, Germany 2 Institute of Pathology, University Hospital Gottingen, Gottingen, Germany 3 Computational Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany 5 Gerhard-Domagk-Institute of Pathology, University Hospital Munster, Munster, Germany Correspondence to: Helen Kunstlinger, email: // Keywords : myxoid liposarcoma, whole-genome microarray, gene expression, fibroblast growth factor, FGFR inhibition Received : November 20, 2014 Accepted : April 22, 2015 Published : May 08, 2015 Abstract Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R-DDIT3 . The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro , our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors.