Cell
Volume 163, Issue 1, 24 September 2015, Pages 202-217
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Kinome-wide Decoding of Network-Attacking Mutations Rewiring Cancer Signaling

https://doi.org/10.1016/j.cell.2015.08.056Get rights and content
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Highlights

  • Mutations perturbing signaling networks are systematically classified and interpreted

  • Several such functional mutations are identified in cancer and experimentally validated

  • The results suggest that a single point mutant can have profound signaling effects

  • Systematic interpretation of genomic data may assist future precision-medicine efforts

Summary

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.

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

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Present address: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA