BIROn - Birkbeck Institutional Research Online

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

    Nakaoku, T. and Kohno, T. and Araki, M. and Niho, S. and Chauhan, R. and Knowles, P.P. and Tsuchihara, K. and Matsumoto, S. and Shimada, Y. and Mimaki, S. and Ishii, G. and Ichikawa, H. and Nagatoishi, S. and Tsumoto, K. and Okuno, Y. and Yoh, K. and McDonald, Neil Q. and Goto, K. (2018) A secondary RET mutation in the activation loop conferring resistance to vandetanib. Nature Communications 9 (1), p. 625. ISSN 2041-1723.

    [img]
    Preview
    Text
    21358.pdf - Published Version of Record
    Available under License Creative Commons Attribution.

    Download (1MB) | Preview

    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 the 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: Birkbeck Schools and Departments > School of Science > Biological Sciences
    SWORD Depositor: Mr Joe Tenant
    Depositing User: Mr Joe Tenant
    Date Deposited: 13 Mar 2018 17:01
    Last Modified: 30 Jul 2019 05:48
    URI: http://eprints.bbk.ac.uk/id/eprint/21358

    Statistics

    Downloads
    Activity Overview
    91Downloads
    69Hits

    Additional statistics are available via IRStats2.

    Archive Staff Only (login required)

    Edit/View Item Edit/View Item