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

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.

journal_name

EBioMedicine

journal_title

EBioMedicine

authors

Bunney TD,Wan S,Thiyagarajan N,Sutto L,Williams SV,Ashford P,Koss H,Knowles MA,Gervasio FL,Coveney PV,Katan M

doi

10.1016/j.ebiom.2015.02.009

subject

Has Abstract

pub_date

2015-03-01 00:00:00

pages

194-204

issue

3

issn

2352-3964

pii

S2352-3964(15)00057-2

journal_volume

2

pub_type

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