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

Pau Creixell(Technical University of Denmark), Erwin M. Schoof(Technical University of Denmark), Craig D. Simpson(University of Copenhagen), James Longden(University of Copenhagen), Chad J. Miller(Yale University), Hua Jane Lou(Yale University), Lara Perryman(University of Copenhagen), Thomas R. Cox(University of Copenhagen), Nevena Zivanovic(University of Zurich), Antonio Palmeri(University of Rome Tor Vergata), Agata Wesolowska‐Andersen(Technical University of Denmark), Manuela Helmer‐Citterich(University of Rome Tor Vergata), Jesper Ferkinghoff‐Borg(University of Copenhagen), Hiroaki Itamochi(Tottori University), Bernd Bodenmiller(University of Zurich), Janine T. Erler(University of Copenhagen), Benjamin E. Turk(Yale University), Rune Linding(Technical University of Denmark)
Cell
September 1, 2015
10.1016/j.cell.2015.08.056
Cited by 193Open Access
Full Text

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.

Related Papers

A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia identified by Quinacrine Fluorescence and Giemsa Staining
Janet D. Rowley|Nature|1973|4.3k
Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells
Brian Druker, Shu Tamura, Elisabeth Buchdunger et al.|Nature Medicine|1996|3.7k
Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells
A Ullrich, Lisa M. Coussens, Joel S. Hayflick et al.|Nature|1984|2.8k
COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer
Simon Forbes, Nidhi Bindal, Sally Bamford et al.|Nucleic Acids Research|2010|2.3k
Humanization of an anti-p185HER2 antibody for human cancer therapy.
Paul Carter, Leonard G. Presta, C Gorman et al.|Proceedings of the National Academy of Sciences|1992|1.9k