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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Biphenyl Compounds / pharmacology
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Blotting, Western
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cisplatin / pharmacology
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Drug Resistance, Neoplasm / genetics*
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Enzyme Activation / drug effects
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Fibroblast Growth Factor 2 / genetics
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Neuroblastoma / genetics
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Neuroblastoma / metabolism
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Neuroblastoma / pathology
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Nitrophenols / pharmacology
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Oligonucleotide Array Sequence Analysis
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Piperazines / pharmacology
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Protein Kinase C-delta / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrroles / pharmacology
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RNA Interference*
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Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 2 / genetics*
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects
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Signal Transduction / genetics*
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Sulfonamides / pharmacology
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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ABT-737
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Antineoplastic Agents
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BCL2L1 protein, human
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Biphenyl Compounds
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Pyrroles
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SU 5402
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Sulfonamides
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bcl-X Protein
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Fibroblast Growth Factor 2
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FGFR2 protein, human
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Receptor, Fibroblast Growth Factor, Type 2
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Protein Kinase C-delta
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Cisplatin