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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.

<div class='caption-title'>Kinase activity and inhibition of FGFR1 variants.</div>
<div class='caption-title'>Binding of FGFR-inhibitors to wild type (WT) and V561M FGFR1 KD.</div>
<div class='caption-title'>Impact of the gatekeeper substitution V561M on the kinase activity and overall structural changes of FGFR1 KD.</div>
Bunney TD, Wan S, Thiyagarajan N, Sutto L, Williams SV, Ashford P, Koss H, Knowles MA, Gervasio FL, Coveney PV, Katan M
OpenAccess logo EBioMedicine 2 194-204 (2015)
Related entries: 4uwy, 5am7

Cited: 35 times
EuropePMC logo PMID: 26097890

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.

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Reviews citing this publication (8)

  1. Rapid, accurate, precise and reproducible ligand-protein binding free energy prediction. Wan S, Bhati AP, Zasada SJ, Coveney PV. Interface Focus 10 20200007 (2020)
  2. FGFR-TKI resistance in cancer: current status and perspectives. Yue S, Li Y, Chen X, Wang J, Li M, Chen Y, Wu D. J Hematol Oncol 14 23 (2021)
  3. A place for precision medicine in bladder cancer: targeting the FGFRs. di Martino E, Tomlinson DC, Williams SV, Knowles MA. Future Oncol 12 2243-2263 (2016)
  4. Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer. Martin-Fernandez ML, Clarke DT, Roberts SK, Zanetti-Domingues LC, Gervasio FL. Cells 8 E316 (2019)
  5. An overview of the binding models of FGFR tyrosine kinases in complex with small molecule inhibitors. Cheng W, Wang M, Tian X, Zhang X. Eur J Med Chem 126 476-490 (2017)
  6. Biological Significance and Targeting of the FGFR Axis in Cancer. Chioni AM, Grose RP. Cancers (Basel) 13 5681 (2021)
  7. Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review. Zheng J, Zhang W, Li L, He Y, Wei Y, Dang Y, Nie S, Guo Z. Front Chem 10 860985 (2022)
  8. Structural Alterations in Human Fibroblast Growth Factor Receptors in Carcinogenesis. Mikhaylenko DS, Alekseev BY, Zaletaev DV, Goncharova RI, Nemtsova MV. Biochemistry (Mosc) 83 930-943 (2018)

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