Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma
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 overexpres...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/16/4034 |
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| author | Jerry T. Wu Adam Cheuk Kristine Isanogle Christina Robinson Xiaohu Zhang Michele Ceribelli Erin Beck Paul Shinn Carleen Klumpp-Thomas Kelli M. Wilson Crystal McKnight Zina Itkin Hiroshi Sotome Hiroshi Hirai Elizabeth Calleja Volker Wacheck Brad Gouker Cody J. Peer Natalia Corvalan David Milewski Yong Y. Kim William D. Figg Elijah F. Edmondson Craig J. Thomas Simone Difilippantonio Jun S. Wei Javed Khan |
| author_facet | Jerry T. Wu Adam Cheuk Kristine Isanogle Christina Robinson Xiaohu Zhang Michele Ceribelli Erin Beck Paul Shinn Carleen Klumpp-Thomas Kelli M. Wilson Crystal McKnight Zina Itkin Hiroshi Sotome Hiroshi Hirai Elizabeth Calleja Volker Wacheck Brad Gouker Cody J. Peer Natalia Corvalan David Milewski Yong Y. Kim William D. Figg Elijah F. Edmondson Craig J. Thomas Simone Difilippantonio Jun S. Wei Javed Khan |
| author_sort | Jerry T. Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T00:03:58Z |
| format | Article |
| id | doaj.art-00cb0d46e83f458c957ec5bbe343fd7e |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T00:03:58Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-00cb0d46e83f458c957ec5bbe343fd7e2023-11-19T00:32:10ZengMDPI AGCancers2072-66942023-08-011516403410.3390/cancers15164034Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric RhabdomyosarcomaJerry T. Wu0Adam Cheuk1Kristine Isanogle2Christina Robinson3Xiaohu Zhang4Michele Ceribelli5Erin Beck6Paul Shinn7Carleen Klumpp-Thomas8Kelli M. Wilson9Crystal McKnight10Zina Itkin11Hiroshi Sotome12Hiroshi Hirai13Elizabeth Calleja14Volker Wacheck15Brad Gouker16Cody J. Peer17Natalia Corvalan18David Milewski19Yong Y. Kim20William D. Figg21Elijah F. Edmondson22Craig J. Thomas23Simone Difilippantonio24Jun S. Wei25Javed Khan26Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USATaiho Pharmaceutical Co., Ltd., Tsukuba 300-0034, JapanTaiho Pharmaceutical Co., Ltd., Tsukuba 300-0034, JapanTaiho Oncology, Princeton, NJ 08540, USATaiho Oncology, Princeton, NJ 08540, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USAClinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAClinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAClinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USANational Center for Advancing Translational Sciences, Rockville, MD 20850, USALaboratory Animal Sciences Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USAGenetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USARhabdomyosarcoma (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.https://www.mdpi.com/2072-6694/15/16/4034rhabdomyosarcomaFGFR4FGFR inhibitorfutibatinibpediatric cancer |
| spellingShingle | Jerry T. Wu Adam Cheuk Kristine Isanogle Christina Robinson Xiaohu Zhang Michele Ceribelli Erin Beck Paul Shinn Carleen Klumpp-Thomas Kelli M. Wilson Crystal McKnight Zina Itkin Hiroshi Sotome Hiroshi Hirai Elizabeth Calleja Volker Wacheck Brad Gouker Cody J. Peer Natalia Corvalan David Milewski Yong Y. Kim William D. Figg Elijah F. Edmondson Craig J. Thomas Simone Difilippantonio Jun S. Wei Javed Khan Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma Cancers rhabdomyosarcoma FGFR4 FGFR inhibitor futibatinib pediatric cancer |
| title | Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma |
| title_full | Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma |
| title_fullStr | Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma |
| title_full_unstemmed | Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma |
| title_short | Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma |
| title_sort | preclinical evaluation of the fgfr family inhibitor futibatinib for pediatric rhabdomyosarcoma |
| topic | rhabdomyosarcoma FGFR4 FGFR inhibitor futibatinib pediatric cancer |
| url | https://www.mdpi.com/2072-6694/15/16/4034 |
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