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Fibroblast growth factor receptors as novel therapeutic targets in malignant rhabdoid tumors

Woehrle, Simon and Weiss, Andreas and Ito, Moriko and Kauffmann, Audrey and Murakami, Masato and Jagani, Zainab and Thuery, Anne and Bauer-Probst, Beatrice and Reimann, Flavia and Stamm, Christelle and Pornon, Astrid and Guagnano, Vito and Bruemmendorf, Thomas and Sellers, William and Hofmann, Francesco and Roberts, Charles W. M. and Graus Porta, Diana (2013) Fibroblast growth factor receptors as novel therapeutic targets in malignant rhabdoid tumors. PLoS ONE, 8 (10). e77652-e77652. ISSN 1932-6203

Abstract

Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric cancers arising in brain, kidney and soft tissues, which are characterized by loss of the tumor suppressor SNF5. MRTs are poorly responsive to chemotherapy and thus a high unmet clinical need exists for novel therapies for MRT patients. SNF5 is a core subunit of the SWI/SNF chromatin remodeling complex which affects gene expression by nucleosome remodeling. In this study, we report that loss of SNF5 function correlates with increased expression of fibroblast growth factor receptors (FGFRs) in MRT cell lines and primary tumor samples and that re-expression of SNF5 in MRT cell lines causes a striking repression of FGFR expression. Conversely, siRNA-mediated impairment of SWI/SNF function leads to elevated levels of FGFR2 in human fibroblast. In vivo, treatment with NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor, blocks progression of a MRT allograft derived from a SNF5-deficient mouse model. Hence, we identify FGFR signaling as an aberrantly activated oncogenic pathway in MRTs and propose pharmacological inhibition of FGFRs as a potential novel clinical therapy for MRTs.

Item Type: Article
Date Deposited: 13 Apr 2017 00:45
Last Modified: 13 Apr 2017 00:45
URI: https://oak.novartis.com/id/eprint/8933

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