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Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma

  1. Author:
    Wu, Jerry T
    Cheuk, Adam
    Isanogle,Kristine
    Robinson,Christina
    Zhang, Xiaohu
    Ceribelli, Michele
    Beck, Erin
    Shinn, Paul
    Klumpp-Thomas, Carleen
    Wilson, Kelli M [ORCID]
    McKnight, Crystal
    Itkin, Zina
    Sotome, Hiroshi
    Hirai, Hiroshi
    Calleja, Elizabeth
    Wacheck, Volker
    Gouker, Brad
    Peer, Cody J [ORCID]
    Corvalan, Natalia [ORCID]
    Milewski, David [ORCID]
    Kim, Yong Y
    Figg, William D [ORCID]
    Edmondson,Elijah [ORCID]
    Thomas, Craig J
    Difilippantonio,Simone
    Wei, Jun S [ORCID]
    Khan, Javed [ORCID]

  2. Author Address

    Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Laboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., National Center for Advancing Translational Sciences, Rockville, MD 20850, USA., Taiho Pharmaceutical Co., Ltd., Tsukuba 300-0034, Japan., Taiho Oncology, Princeton, NJ 08540, USA., Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.,
    1. Year: 2023
    2. Date: Aug 09
    3. Epub Date: 2023 08 09
  2. Journal: Cancers
    1. 15
    2. 16
  4. Type of Article: Article
  5. Article Number: 4034
  1. Abstract:

    Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.

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External Sources

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  2. DOI: 10.3390/cancers15164034
  3. PMID: 37627061
  4. PMCID: PMC10452847
  5. PII : cancers15164034

Library Notes

  1. Fiscal Year: FY2022-2023
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