Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

Pau Creixell, Erwin M Schoof, Craig D. Simpson, James Longden, Chad J. Miller, Hua Jane Lou, Lara Perryman, Thomas R Cox, Nevena Zivanovic, Antonio Palmeri, Agata Wesolowska, Manuela Helmer-Citterich, Jesper Ferkinghoff-Borg, Hiroaki Itamochi, Bernd Bodenmiller, Janine T. Erler, Benjamin E. Turk, Rune Linding

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    Abstract

    Cancer cells acquire pathological phenotypes through accumulation of mutations that perturb signaling networks. However, global analysis of these events is currently limited. Here, we identify six types of network-attacking mutations (NAMs), including changes in kinase and SH2 modulation, network rewiring, and the genesis and extinction of phosphorylation sites. We developed a computational platform (ReKINect) to identify NAMs and systematically interpreted the exomes and quantitative (phospho-)proteomes of five ovarian cancer cell lines and the global cancer genome repository. We identified and experimentally validated several NAMs, including PKCγ M501I and PKD1 D665N, which encode specificity switches analogous to the appearance of kinases de novo within the kinome. We discover mutant molecular logic gates, a drift toward phospho-threonine signaling, weakening of phosphorylation motifs, and kinase-inactivating hotspots in cancer. Our method pinpoints functional NAMs, scales with the complexity of cancer genomes and cell signaling, and may enhance our capability to therapeutically target tumor-specific networks.
    Original languageEnglish
    JournalCELL
    Volume163
    Issue number1
    Pages (from-to)202-217
    Number of pages16
    ISSN0092-8674
    DOIs
    Publication statusPublished - 2015

    Bibliographical note

    This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

    Cite this

    Creixell, P., Schoof, E. M., Simpson, C. D., Longden, J., Miller, C. J., Lou, H. J., Perryman, L., Cox, T. R., Zivanovic, N., Palmeri, A., Wesolowska, A., Helmer-Citterich, M., Ferkinghoff-Borg, J., Itamochi, H., Bodenmiller, B., Erler, J. T., Turk, B. E., & Linding, R. (2015). Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling. CELL, 163(1), 202-217. https://doi.org/10.1016/j.cell.2015.08.056