2. Academic Validation
  3. Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations

Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations

  • Nat Genet. 2025 Dec 8. doi: 10.1038/s41588-025-02431-8.
Carla Tangermann 1 2,  Avantika Ghosh 1 2,  Martin Ziegler 3 4,  Francesco Facchinetti 5,  Jannis Stappenbeck 1,  Yagmur Oyku Carus Sahin 1 2,  Marisa Riester 1,  Luise Carmina Viardot 1,  Tobias Zundel 1,  Luc Friboulet 5,  Antoine Hollebecque 6 7,  José J Naveja 8 9,  Angela Wanninger 1 2,  Maria Elena Hess 10 11,  Tilman Brummer 2 12,  Melanie Boerries 2 10,  Sonja Loges 3 4,  Yohann Loriot 5 6 7,  Anna L Illert 2 13 14 15 16,  Sven Diederichs 17 18
Affiliations

Affiliations

  • 1 Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 2 German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany.
  • 3 Division of Personalized Medical Oncology (A420), German Cancer Research Center (DKFZ), Heidelberg, Germany and DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
  • 4 German Cancer Consortium (DKTK), DKFZ core center Heidelberg, Heidelberg, Germany.
  • 5 Université Paris-Saclay, Gustave Roussy, Inserm U981, Villejuif, France.
  • 6 Département d'Innovation Thérapeutique (DITEP), Gustave Roussy, Villejuif, France.
  • 7 Département de Médecine Oncologique, Gustave Roussy, Villejuif, France.
  • 8 3rd Medical Department and University Cancer Center, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
  • 9 Institute of Molecular Biology (IMB) gGmbH, Mainz, Germany.
  • 10 Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 11 Faculty of Biology, University of Freiburg, Freiburg, Germany.
  • 12 Institute of Molecular Medicine and Cell Research (IMMZ), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 13 Internal Medicine III, Hematology and Medical Oncology, School of Medicine, Technical University Munich, Munich, Germany.
  • 14 German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and Technical University Munich, Munich, Germany.
  • 15 Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
  • 16 Department of Hematology and Medical Oncology, University Medical Center Göttingen (UMG), Göttingen, Germany.
  • 17 Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [email protected].
  • 18 German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and University Medical Center Freiburg, Freiburg, Germany. [email protected].
PMID: 41361008 DOI: 10.1038/s41588-025-02431-8
Abstract

Variants of uncertain significance represent the biggest challenge for genomics-based precision oncology. Activated Fibroblast Growth Factor receptors (FGFRs) frequently drive tumorigenesis by different genetic aberrations. However, it remains unknown which of the many point mutations affecting FGFR1, FGFR2, FGFR3 or FGFR4 in Cancer are druggable, that is, activating signaling while not mediating FGFR Inhibitor resistance. Here we implemented a saturation mutational scanning platform to screen all 11,520 possible point mutations covering the kinase domains of FGFR1-4. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable FGFR mutations analogous to a strong PS3/BS3 evidence level. The screens also identified loss-of-function mutations and an association of gain-of-function mutations with hydrophobic changes. The functional screens identified 97% of acquired resistance mutations in clinical trials. Our comprehensive catalog of every druggable mutation in the FGFR kinase domains is readily available for clinical decision support.

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