Novel multiple tyrosine kinase inhibitor ponatinib inhibits bFGF-activated signaling in neuroblastoma cells and suppresses neuroblastoma growth in vivo.

Abstract	Neuroblastoma (NB) is one of the most common pediatric malignancies in children. Abnormal activation of receptor tyrosine kinases contributes to the pathological development of NB. Therefore, targeting tyrosine kinase receptors to cure NB is a promising strategy. Here, we report that a multi-targeted tyrosine kinase inhibitor ponatinib inhibited NB cell proliferation and induced NB cell apoptosis in a dose-dependent manner. In addition, ponatinib suppressed the colony formation ability of NB cells. Mechanistically, ponatinib effectively inhibited the FGFR1-activated signaling pathway. Ponatinib also enhanced the cytotoxic effects of doxorubicin on NB cells. Furthermore, ponatinib demonstrated anti-tumor efficacy in vivo by inhibiting tumor growth in an orthotopic xenograft NB mouse model. In summary, our results showed that ponatinib inhibited NB growth both in vitro and in vivo.
Authors	Haoyu Li, Yongfeng Wang, Zhenghu Chen, Jiaxiong Lu, Jessie Pan, Yang Yu, Yanling Zhao, Huiyuan Zhang, Ting Hu, Qing Liu, Jianhua Yang
Journal	Oncotarget (Oncotarget) Vol. 8 Issue 4 Pg. 5874-5884 (Jan 24 2017) ISSN: 1949-2553 [Electronic] United States
PMID	27564113 (Publication Type: Journal Article)
Chemical References	Imidazoles Protein Kinase Inhibitors Pyridazines Fibroblast Growth Factor 2 ponatinib FGFR1 protein, human Receptor, Fibroblast Growth Factor, Type 1 Doxycycline
Topics	Animals Cell Line, Tumor Cell Proliferation (drug effects) Cell Survival (drug effects) Dose-Response Relationship, Drug Doxycycline (administration & dosage, pharmacology) Drug Synergism Fibroblast Growth Factor 2 (metabolism) Gene Expression Regulation, Neoplastic (drug effects) Humans Imidazoles (administration & dosage, pharmacology) Mice Neuroblastoma (drug therapy, metabolism) Protein Kinase Inhibitors (administration & dosage, pharmacology) Pyridazines (administration & dosage, pharmacology) Receptor, Fibroblast Growth Factor, Type 1 (metabolism) Signal Transduction (drug effects) Xenograft Model Antitumor Assays

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