title: Kinome-wide decoding of network-attacking mutations rewiring cancer signaling.
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.
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Pau
authors.initials: P
authors.lastname: Creixell
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Erwin M
authors.initials: EM
authors.lastname: Schoof
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Simpson
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: James
authors.initials: J
authors.lastname: Longden
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Miller
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hua Jane
authors.initials: HJ
authors.lastname: Lou
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Lara
authors.initials: L
authors.lastname: Perryman
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cox
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Nevena
authors.initials: N
authors.lastname: Zivanovic
authors.affiliation: Centre for Molecular Bioinformatics, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palmeri
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark.
authors.forename: Agata
authors.initials: A
authors.lastname: Wesolowska-Andersen
authors.affiliation: Centre for Molecular Bioinformatics, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Helmer-Citterich
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Jesper
authors.initials: J
authors.lastname: Ferkinghoff-Borg
authors.affiliation: Tottori University School of Medicine, Yonago 683-8504, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Bodenmiller
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark.
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Benjamin E
authors.initials: BE
authors.lastname: Turk
authors.affiliation: Department of Systems Biology, Technical University of Denmark, 2800 Lyngby, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen (UCPH), 2200 Copenhagen, Denmark. Electronic address: linding@lindinglab.org.
authors.forename: Rune
authors.initials: R
authors.lastname: Linding
mesh_terms: D005260:Female; D006801:Humans; D016247:Information Storage and Retrieval; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017354:Point Mutation; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012984:Software
chemical_list: D011494:Protein Kinases