Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma

Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We here sought to examine whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome of these patients. Ectopic expression of FGFR1N546K induced constitutive down-stream signaling and interleukin-3-independent growth in Ba/F3 cells, indicating oncogene addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1 mutant high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K mutant neuroblastoma cells, and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma that is associated with failure of current standard chemotherapy, and suggest potential clinical benefit of FGFR-directed therapies in FGFR1 mutant high-risk patients.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2026-02-12
DOI
https://doi.org/10.1172/jci189152
Primary Topic
Neuroblastoma Research and Treatments
Type
article
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article

Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma

Anton George Henssen, Neerav Narendra Shukla, Boris Decarolis, Rochelle Bagatell et al.
Journal of Clinical Investigation
Neuroblastoma Research and Treatments
article

Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma

Anton George Henssen, Neerav Narendra Shukla, Boris Decarolis, Rochelle Bagatell, Fiorella Iglesias, Barbara Hero, Lisa Werr, Marcel A. Dammert, Stefanie Höppner, Christoph Bartenhagen, Carolina Rosswog, Anne M. Schultheis, Sabine Taschner‐Mandl, Anne Gro W. Rognlien, Klaus Beiske, Debbie Hughes, Nadine Hemstedt, Anna‐Maria Hellmann, Josephine Blaamann Petersen, Marie Bernkopf, H Grüll, Sally George, Olaf Witt, Julien Masliah-Planchon, Kathrin Schramm, J Jaap Molenaar, Jana Boland, Louis Chesler, Lea F. Surrey, Martin Peifer, Karin P.S. Langenberg, Thorsten Simon, Matthias Fischer, Giuseppe Barone, Angelika Eggert, Gudrun Schleiermacher, Roman K. Thomas, Jan-Michael Werner, Johannes H. Schulte, Maria Winther Gunnes, Frank Westermann, Mario Capasso, Nadliv Ibruli, Florian Malchers, Reinhard Büttner, H. Christian Reinhardt
article en

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We here sought to examine whether mutant FGFR1 is an oncogenic driver, a predictive biomarker, and an actionable vulnerability in this malignancy. FGFR1 mutations at p.N546 were associated with high-risk disease and rapid tumor progression, resulting in dismal outcome of these patients. Ectopic expression of FGFR1N546K induced constitutive down-stream signaling and interleukin-3-independent growth in Ba/F3 cells, indicating oncogene addicted proliferation. In FGFR1N546K;MYCN transgenic mice, neuroblastoma developed within the first days of life with fatal outcome within 3 weeks, reflecting the devastating clinical phenotypes of patients with FGFR1 mutant high-risk neuroblastoma. Treatment with FGFR inhibitors impaired proliferation and pathway activation in FGFR1N546K-expressing Ba/F3 and patient-derived FGFR1N546K mutant neuroblastoma cells, and inhibited tumor growth in FGFR1N546K;MYCN transgenic mice and in a chemotherapy-resistant patient-derived xenograft mouse model. In addition, partial regression of FGFR1N546K mutant tumor lesions occurred upon treatment with the FGFR inhibitor futibatinib and low-intensity chemotherapy in a patient with refractory neuroblastoma. Together, our data demonstrate that FGFR1N546K is a strong oncogenic driver in neuroblastoma that is associated with failure of current standard chemotherapy, and suggest potential clinical benefit of FGFR-directed therapies in FGFR1 mutant high-risk patients.

Journal of Clinical Investigation
Oslo University Hospital (NO), Memorial Sloan Kettering Cancer Center (US), Children's Hospital of Philadelphia (US), Institute of Cancer Research (GB), Inserm (FR), University of Cologne (DE), Université Paris Sciences et Lettres (FR), Great Ormond Street Hospital (GB), Hopp Children's Cancer Center Heidelberg (DE), St Anna Children's Hospital (AT), University Children's Hospital Tübingen (DE), Princess Máxima Center (NL), University Hospital Cologne (DE), University College London (GB), University of Duisburg-Essen (DE), University of Naples Federico II (IT), Charité - Universitätsmedizin Berlin (DE), Institut Curie (FR)
Good health and well-being
Openalex Percentile: Top 60%
Neuroblastoma Research and Treatments
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