Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma
| Title: | Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma |
|---|---|
| Authors: | 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.; Fischer, Matthias |
| Publisher Information: | American Society for Clinical Investigation |
| Publication Year: | 2026 |
| Collection: | Max-Delbrueck-Center for Molecular Medicine, Berlin: MDC Repository |
| Subject Terms: | Cancer Research; Topic 2: Molecular Processes and Therapies |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf; other |
| Language: | English |
| Relation: | https://edoc.mdc-berlin.de/id/eprint/26185/1/26185oa.pdf; https://edoc.mdc-berlin.de/id/eprint/26185/2/26185suppl.zip; Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma. 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 Journal of Clinical Investigation 136 (7): e189152. 1 April 2026; PMID:41678281; https://doi.org/10.1172/jci189152 |
| DOI: | 10.1172/jci189152 |
| Availability: | https://edoc.mdc-berlin.de/id/eprint/26185/; https://edoc.mdc-berlin.de/26185/; https://doi.org/10.1172/jci189152 |
| Rights: | cc_by_4 |
| Accession Number: | edsbas.82FBA86A |
| Database: | BASE |