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EBioMedicine. 2015 Mar 1;2(3):194-204.

The Effect of Mutations on Drug Sensitivity and Kinase Activity of Fibroblast Growth Factor Receptors: A Combined Experimental and Theoretical Study.

Author information

1
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St., London WC1E 6BT, UK.
2
Centre for Computational Science, Department of Chemistry, University College London, 20 Gordon St., London WC1H 0AJ, UK.
3
Institute of Structural and Molecular Biology, Department of Chemistry, University College London, Gower St., London WC1E 6BT, UK.
4
Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.
5
Institute of Structural and Molecular Biology, Division of Biosciences, University College London, Gower St., London WC1E 6BT, UK ; Division of Molecular Structure, MRC-National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.

Abstract

Fibroblast growth factor receptors (FGFRs) are recognized therapeutic targets in cancer. We here describe insights underpinning the impact of mutations on FGFR1 and FGFR3 kinase activity and drug efficacy, using a combination of computational calculations and experimental approaches including cellular studies, X-ray crystallography and biophysical and biochemical measurements. Our findings reveal that some of the tested compounds, in particular TKI258, could provide therapeutic opportunity not only for patients with primary alterations in FGFR but also for acquired resistance due to the gatekeeper mutation. The accuracy of the computational methodologies applied here shows a potential for their wider application in studies of drug binding and in assessments of functional and mechanistic impacts of mutations, thus assisting efforts in precision medicine.

KEYWORDS:

Cancer; Clinical inhibitors; FGFR; Resistance mutations

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