title: Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
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.
authors.affiliation: Oncogenomics Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Samuel Q
authors.initials: SQ
authors.lastname: Li
authors.forename: Adam T
authors.initials: AT
authors.lastname: Cheuk
authors.forename: Jack F
authors.initials: JF
authors.lastname: Shern
authors.forename: Young K
authors.initials: YK
authors.lastname: Song
authors.forename: Laura
authors.initials: L
authors.lastname: Hurd
authors.forename: Hongling
authors.initials: H
authors.lastname: Liao
authors.forename: Jun S
authors.initials: JS
authors.lastname: Wei
authors.forename: Javed
authors.initials: J
authors.lastname: Khan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D012208:Rhabdomyosarcoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D050796:STAT3 Transcription Factor; C545373:ponatinib; D051499:Receptor, Fibroblast Growth Factor, Type 4