RRC ID 44698
著者 Li SQ, Cheuk AT, Shern JF, Song YK, Hurd L, Liao H, Wei JS, Khan J.
タイトル Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
ジャーナル PLoS One
Abstract Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.
巻・号 8(10)
ページ e76551
公開日 2013-1-1
DOI 10.1371/journal.pone.0076551
PII PONE-D-13-16057
PMID 24124571
PMC PMC3790700
MeSH Animals Apoptosis / drug effects Apoptosis / genetics Cell Cycle / drug effects Cell Cycle / genetics Cell Line Disease Models, Animal Drug Resistance, Neoplasm / genetics Female Gene Expression Humans Imidazoles / pharmacology* Mice Mutation Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology* Pyridazines / pharmacology* Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors* Receptor, Fibroblast Growth Factor, Type 4 / genetics Receptor, Fibroblast Growth Factor, Type 4 / metabolism* Rhabdomyosarcoma / drug therapy Rhabdomyosarcoma / genetics Rhabdomyosarcoma / metabolism* Rhabdomyosarcoma / pathology STAT3 Transcription Factor / metabolism Tumor Burden / drug effects Tumor Burden / genetics
IF 2.74
引用数 26
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 Ba/F3(RCB0805)