Mutated FGFR1 is an oncogenic driver and therapeutic target in high-risk neuroblastoma
Lisa Werr, et al.
Lisa Werr, et al.
View: Text | PDF
Research Article Cell biology Oncology

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

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.

Authors

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

×

Figure 8

Futibatinib impairs tumor growth and prolongs survival in FGFR1N546K;MYCN transgenic mice.

Options: View larger image (or click on image) Download as PowerPoint
Futibatinib impairs tumor growth and prolongs survival in FGFR1N546K;MYC...
(A) Temporal changes of relative tumor diameters in R26-FGFR1N546K/wt;Th-IRES-Cretg/wt;Th-MYCNtg/wt mice treated with 5 mg/kg futibatinib (light green), 30 mg/kg futibatinib (dark green), or control substance (0.5% CMC-Na; blue). Growth curves of individual tumors are shown on the left; mean and range of the relative tumor diameter changes are shown on the right. (B) OS of R26-FGFR1N546K/wt;Th-IRES-Cretg/wt;Th-MYCNtg/wt mice treated with 5 mg/kg, or 30 mg/kg futibatinib, or control. Survival of mice treated with 5 mg/kg futibatinib was significantly longer than that of control mice (P < 0.001), whereas survival of mice treated with 30 mg/kg futibatinib was not significantly prolonged, due to toxicity (P = 0.47). (C) Axial T2-weighted MRI scans of an R26-FGFR1N546K/wt;Th-IRES-Cretg/wt;Th-MYCNtg/wt mouse treated with 5 mg/kg futibatinib at the indicated ages. (D) H&E and PHOX2B, Ki67, and CC3 immunohistochemical staining of tumor sections obtained from R26-FGFR1N546K/wt;Th-IRES-Cretg/wt;Th-MYCNtg/wt mice treated with control (top) or 5 mg/kg futibatinib (bottom); scale bar, 50 μm. (E) Absolute volumes of tumors obtained from R26-FGFR1N546K/wt;Th-IRES-Cretg/wt;Th-MYCNtg/wt mice, subcutaneously reimplanted into NSG mice and treated with 10 mg/kg futibatinib (n = 11) or control (n = 9) after reaching a volume of 0.08–0.2 cm3. Growth curves of individual tumors are shown on the left; mean and range of tumor volumes are shown on the right.