![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
Preview |
PDF (Original Article)
- Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
19MB |
![[thumbnail of Supplementary Material]](https://edoc.mdc-berlin.de/style/images/fileicons/other.png) |
Other (Supplementary Material)
39MB |
| Item Type: | Article |
|---|---|
| Title: | Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma |
| Creators Name: | Werr, Lisa, Boland, Jana, Petersen, Josephine, Iglesias, Fiorella, Höppner, Stefanie, Bartenhagen, Christoph, Rosswog, Carolina, Hellmann, Anna-Maria, Kahlert, Yvonne, Hemstedt, Nadine, Ibruli, Nadliv, Dammert, Marcel A., Decarolis, Boris, Werner, Jan-Michael, Malchers, Florian, Schramm, Kathrin, Witt, Olaf, Beiske, Klaus Hermann, Rognlien, Anne Gro Wesenberg, Gunnes, Maria Winther, Langenberg, Karin Ps, Molenaar, Jan, Bernkopf, Marie, Taschner-Mandl, Sabine, Hughes, Debbie, George, Sally L., Chesler, Louis, Schulte, Johannes H., Barone, Giuseppe, Capasso, Mario, Surrey, Lea F., Bagatell, Rochelle, Masliah-Planchon, Julien, Schleiermacher, Gudrun, Grüll, Holger, Westermann, Frank, Schultheis, Anne M., Büttner, Reinhard, Henssen, Anton G., Eggert, Angelika, Peifer, Martin, Shukla, Neerav N., Simon, Thorsten, Hero, Barbara, Reinhardt, H. Christian, Thomas, Roman K. and Fischer, Matthias |
| 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 FGFR1(N546K) induced constitutive downstream signaling and IL-3–independent growth in Ba/F3 cells, indicating oncogene-addicted proliferation. In FGFR1(N546K);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 FGFR1(N546K)-expressing Ba/F3 and patient-derived FGFR1(N546K)-mutant neuroblastoma cells and inhibited tumor growth in FGFR1(N546K);MYCN transgenic mice and in a chemotherapy-resistant, patient-derived xenograft mouse model. In addition, partial regression of FGFR1(N546K)-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 FGFR1(N546K) 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. |
| Keywords: | Amino Acid Substitution, Missense Mutation, Mutation, Neoplasm Proteins, Neuroblastoma, Transgenic Mice, Tumor Cell Line, Type 1 Fibroblast Growth Factor Receptor, Xenograft Model Antitumor Assays, Animals, Mice |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 136 |
| Number: | 7 |
| Page Range: | e189152 |
| Date: | 1 April 2026 |
| Official Publication: | https://doi.org/10.1172/jci189152 |
| PubMed: | View item in PubMed |
| Related to: |
Repository Staff Only: item control page
