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

Citations Over TimeTop 1% of 2015 papers

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 Targeted Quantitative Proteomics Strategy for Global Kinome Profiling of Cancer Cells and Tissues(2014)53 cited
• → Mapping the Protein Kinome: Current Strategy and Future Direction(2023)5 cited
• → “Going KiNativ”: Probing the Native Kinome(2011)12 cited
• → Abstract B23: Reprogramming of the cancer kinome in response to targeted kinase inhibition(2012)
• → Abstract PO-075: Kinotype to phenotype: Perturbed phosphoproteomic state predicts cancer cell growth rates in vitro(2021)