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    Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer

    Plenker, D. and Riedel, M. and Brägelmann, J. and Dammert, M.A. and Chauhan, R. and Knowles, P.K. and Lorenz, C. and Keul, M. and Bührmann, M. and Pagel, O. and Tischler, V. and Scheel, A.H. and Schütte, D. and Song, Y. and Stark, J. and Mrugalla, F. and Alber, Y. and Richters, A. and Engel, J. and Leenders, F. and Heuckmann, J.M. and Wolf, J. and Diebold, J. and Pall, G. and Peifer, M. and Aerts, M. and Gevaert, K. and Zahedi, R.P. and Buettner, R. and Shokat, K.M. and McDonald, Neil Q. and Kast, S.M. and Gautschi, O. and Thomas, R.K. and Sos, M.L. (2017) Mechanistic insight into RET kinase inhibitors targeting the DFG-out conformation in RET-rearranged cancer. Science Translational Medicine 9 (394), ISSN 1946-6234.

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    Abstract

    Oncogenic fusion events have been identified in a broad range of tumors. Among them, RET rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. Here, we provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors such as AD80 or ponatinib that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill RET-rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in RET-rearranged cells we identify the CCDC6-RETI788N mutation and drug-induced MAPK pathway reactivation as possible mechanisms, by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.

    Metadata

    Item Type: Article
    Additional Information: This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published at the link above. Supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001115), the UK Medical Research Council (FC001115) and the Wellcome Trust (FC001115); by the NCI/NIH (grant reference 5R01CA197178); by the Association f
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Neil Mcdonald
    Date Deposited: 09 Jan 2018 10:58
    Last Modified: 28 Sep 2018 13:07
    URI: http://eprints.bbk.ac.uk/id/eprint/18406

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