弗莱堡大学Sven Diederichs团队宣布他们的最新研究揭示了饱和诱变识别激活和抗性诱导的FGFR激酶结构域突变。相关论文发表在2025年12月8日出版的《自然—遗传学》杂志上。

在这里，研究团队实现了一个饱和突变扫描平台来筛选覆盖FGFR1-4激酶结构域的所有11520个可能的点突变。合并阳性选择筛选确定了474个激活突变和738个突变介导对FGFR抑制剂培伽替尼和福替替尼的耐药，共同揭示了301个可用药的FGFR突变类似于它们，达到了强有力的PS3/BS3证据水平。筛选还发现了功能丧失突变和功能获得突变与疏水变化的关联。在临床试验中，功能性筛选确定了97%的获得性耐药突变。他们对FGFR激酶结构域中每个可用药突变的综合目录很容易用于临床决策支持。

据悉，意义不确定的变异是基于基因组学的精确肿瘤学面临的最大挑战。激活的成纤维细胞生长因子受体（FGFRs）经常通过不同的遗传畸变驱动肿瘤发生。然而，目前尚不清楚在癌症中影响FGFR1、FGFR2、FGFR3或FGFR4的许多点突变中，哪些是可药物性的，即激活信号而不介导FGFR抑制剂耐药性。

附：英文原文

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

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

Issue&Volume: 2025-12-08

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.

DOI: 10.1038/s41588-025-02431-8

Source: https://www.nature.com/articles/s41588-025-02431-8