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    A secondary RET mutation in the activation loop conferring resistance to vandetanib

    Kohno, T. and McDonald, Neil Q. (2018) A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nature Communications 9 , p. 625. ISSN 2041-1723.

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    Abstract

    Resistance to vandetanib, a type I RET kinase inhibitor, developed in a patient with metastatic lung adenocarcinoma harboring a CCDC6-RET fusion that initially exhibited a response to treatment. The resistant tumor acquired a secondary mutation resulting in a serine-to-phenylalanine substitution at codon 904 in the activation loop of the RET kinase domain. The S904F mutation confers resistance to vandetanib by increasing the ATP affinity and autophosphorylation activity of RET kinase. A reduced interaction with drug is also observed in vitro for the S904F mutant by thermal shift assay. A crystal structure of the S904F mutant reveals a small hydrophobic core around F904 likely to enhance basal kinase activity by stabilizing an active conformer. Our findings indicate that missense mutations in the activation loop of the kinase domain are able to increase kinase activity and confer drug resistance through allosteric effects.

    Metadata

    Item Type: Article
    School: School of Science > Biological Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Neil McDonald
    Date Deposited: 29 Mar 2019 13:13
    Last Modified: 15 Feb 2021 01:48
    URI: https://eprints.bbk.ac.uk/id/eprint/20758

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