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

Salm, F; Cwiek, P; Ghosal, A; Lucia Buccarello, A; Largey, F; Wotzkow, C; Höland, K; Styp-Rekowska, B; Djonov, V; Zlobec, I; Bodmer, N; Gross, N; Westermann, F; Schäfer, S C; Arcaro, A (2012). RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance. Oncogene, 32(34), pp. 3944-3953. Basingstoke, UK: Nature Publishing Group 10.1038/onc.2012.416

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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 BCLX(L). 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.Oncogene advance online publication, 1 October 2012; doi:10.1038/onc.2012.416.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Salm, Fabiana; Höland, Katrin; Djonov, Valentin; Zlobec, Inti and Arcaro, Alexandre

ISSN:

0950-9232

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:32

Last Modified:

02 Apr 2014 16:18

Publisher DOI:

10.1038/onc.2012.416

PubMed ID:

23027129

Web of Science ID:

000323748100003

URI:

https://boris.unibe.ch/id/eprint/12495 (FactScience: 218847)

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