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<p>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 <i>FGFR1</i>, <i>FGFR2</i>, <i>FGFR3</i> or <i>FGFR4</i> 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 <i>FGFR1</i>–<i>4</i>. Pooled positive selection screens identified 474 activating and 738 mutations mediating resistance to the FGFR inhibitors pemigatinib and futibatinib, together revealing 301 druggable <i>FGFR</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Carla Tangermann,
  • Avantika Ghosh,
  • Martin Ziegler,
  • Francesco Facchinetti,
  • Jannis Stappenbeck,
  • Yagmur Oyku Carus Sahin,
  • Marisa Riester,
  • Luise Carmina Viardot,
  • Tobias Zundel,
  • Luc Friboulet,
  • Antoine Hollebecque,
  • José J. Naveja,
  • Angela Wanninger,
  • Maria Elena Hess,
  • Tilman Brummer,
  • Melanie Boerries,
  • Sonja Loges,
  • Yohann Loriot,
  • Anna L. Illert,
  • Sven Diederichs

摘要

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.