Related Experiment Video
Updated: Jan 9, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations
Carla Tangermann1,2, Avantika Ghosh1,2, Martin Ziegler3,4
1Division of Cancer Research, Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
This study identifies druggable mutations in fibroblast growth factor receptors (FGFRs) crucial for precision oncology. It provides a comprehensive catalog of FGFR mutations that activate signaling without causing resistance to inhibitors, aiding clinical decisions.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- Variants of uncertain significance pose challenges in genomics-based precision oncology.
- Activated fibroblast growth factor receptors (FGFRs) drive tumorigenesis through various genetic aberrations.
- Identifying druggable FGFR mutations is critical for targeted cancer therapies.
Purpose of the Study:
- To systematically screen all possible point mutations in FGFR1-4 kinase domains.
- To identify activating and resistance mutations for FGFR inhibitors.
- To create a comprehensive catalog of druggable FGFR mutations for clinical decision support.
Main Methods:
- Implemented a saturation mutational scanning platform.
- Utilized pooled positive selection screens to identify mutation effects.
- Tested mutations against FGFR inhibitors pematinib and futibatinib.
Main Results:
- Screened 11,520 possible point mutations across FGFR1-4 kinase domains.
- Identified 474 activating mutations and 738 resistance mutations.
- Cataloged 301 druggable FGFR mutations with strong evidence, including 97% of acquired resistance mutations from clinical trials.
Conclusions:
- A comprehensive catalog of druggable FGFR mutations was generated.
- This resource aids in clinical decision-making for precision oncology.
- The study provides insights into FGFR mutation types and their functional consequences.
More Related Videos
11:49A Novel Saturation Mutagenesis Approach: Single Step Characterization of Regulatory Protein Binding Sites in RNA Using Phosphorothioates
Published on: August 21, 2018
15:05Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Related Concept Videos
01:39Mutations
01:35Mutations
Chromosomal Alterations Are Large-Scale Mutations
While point mutations are changes in a single nucleotide in...
01:30Spontaneous and Induced Mutations