RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2013-08

AUTHORS

F Salm, P Cwiek, A Ghosal, A Lucia Buccarello, F Largey, C Wotzkow, K Höland, B Styp-Rekowska, V Djonov, I Zlobec, N Bodmer, N Gross, F Westermann, S C Schäfer, A Arcaro

ABSTRACT

Chemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLXL. Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB. More... »

PAGES

3944

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2012.416

DOI

http://dx.doi.org/10.1038/onc.2012.416

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1046369944

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/23027129


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