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| Home > Publications database > Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma. |
| Home > Publications database > Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma. |
| Journal Article | DKFZ-2026-00774 |
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2026
ASCJ
Ann Arbor, Mich.
Abstract: Fibroblast growth factor receptor 1 (FGFR1) is recurrently mutated at p.N546 in neuroblastoma. We examined 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 for these patients. Ectopic expression of FGFR1N546K induced constitutive downstream signaling and IL-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 associated with failure of current standard chemotherapy and suggest potential clinical benefit of FGFR-directed therapies in patients with high-risk mutant FGFR1.
Keyword(s): Neuroblastoma: genetics (MeSH) ; Neuroblastoma: drug therapy (MeSH) ; Neuroblastoma: metabolism (MeSH) ; Neuroblastoma: pathology (MeSH) ; Receptor, Fibroblast Growth Factor, Type 1: genetics (MeSH) ; Receptor, Fibroblast Growth Factor, Type 1: metabolism (MeSH) ; Receptor, Fibroblast Growth Factor, Type 1: antagonists & inhibitors (MeSH) ; Animals (MeSH) ; Humans (MeSH) ; Mice (MeSH) ; Mice, Transgenic (MeSH) ; Cell Line, Tumor (MeSH) ; Mutation (MeSH) ; Neoplasm Proteins: genetics (MeSH) ; Neoplasm Proteins: metabolism (MeSH) ; Neoplasm Proteins: antagonists & inhibitors (MeSH) ; Mutation, Missense (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Female (MeSH) ; Amino Acid Substitution (MeSH) ; Cancer ; Cell biology ; Mouse models ; Oncology ; Receptor, Fibroblast Growth Factor, Type 1 ; FGFR1 protein, human ; Neoplasm Proteins ; Fgfr1 protein, mouse
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