RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses.
de Bono, J
MetadataShow full item record
<h4>Background</h4>F-box and WD40 repeat domain-containing 7 (FBXW7) is an E3 ubiquitin ligase involved in the ubiquitination and degradation of multiple oncogenic substrates. The tumour suppressor function is frequently lost in multiple cancers through genetic deletion and mutations in a broad range of tumours. Loss of FBXW7 functionality results in the stabilisation of multiple major oncoproteins, culminating in increased cellular proliferation and pro-survival pathways, cell cycle deregulation, chromosomal instability and altered metabolism. Currently, there is no therapy to specifically target FBXW7-deficient tumours.<h4>Methods</h4>We performed a siRNA kinome screen to identify synthetically lethal hits to FBXW7 deficiency.<h4>Results</h4>We identified and validated cyclin G-associated kinase (GAK) as a potential new therapeutic target. Combined loss of FBXW7 and GAK caused cell cycle defects, formation of multipolar mitoses and the induction of apoptosis. The synthetic lethal mechanism appears to be independent of clathrin-mediated receptor endocytosis function of GAK.<h4>Conclusions</h4>These data suggest a putative therapeutic strategy for a large number of different types of human cancers with FBXW7 loss, many of which have a paucity of molecular abnormalities and treatment options.
Version of record
Cell Line, Tumor
Intracellular Signaling Peptides and Proteins
Cell Cycle Proteins
RNA, Small Interfering
Synthetic Lethal Mutations
F-Box-WD Repeat-Containing Protein 7
Drug Target Discovery
Signal Transduction & Molecular Pharmacology
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
License start date
British journal of cancer, 2017, 117 (7), pp. 954 - 964
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0
Showing items related by title, author, creator and subject.
Structural Basis for Auto-Inhibition of the NDR1 Kinase Domain by an Atypically Long Activation Segment. Xiong, S; Lorenzen, K; Couzens, AL; Templeton, CM; Rajendran, D; Mao, DYL; Juang, Y-C; Chiovitti, D; Kurinov, I; Guettler, S; Gingras, A-C; Sicheri, F (2018-08)The human NDR family kinases control diverse aspects of cell growth, and are regulated through phosphorylation and association with scaffolds such as MOB1. Here, we report the crystal structure of the human NDR1 kinase ...
Phosphorylation-mediated interactions with TOPBP1 couple 53BP1 and 9-1-1 to control the G1 DNA damage checkpoint. Bigot, N; Day, M; Baldock, RA; Watts, FZ; Oliver, AW; Pearl, LH (2019-05-28)Coordination of the cellular response to DNA damage is organised by multi-domain 'scaffold' proteins, including 53BP1 and TOPBP1, which recognise post-translational modifications such as phosphorylation, methylation and ...
Martino, F; Pal, M; Muñoz-Hernández, H; Rodríguez, CF; Núñez-Ramírez, R; Gil-Carton, D; Degliesposti, G; Skehel, JM; Roe, SM; Prodromou, C; Pearl, LH; Llorca, O (2018-04-16)The R2TP/Prefoldin-like co-chaperone, in concert with HSP90, facilitates assembly and cellular stability of RNA polymerase II, and complexes of PI3-kinase-like kinases such as mTOR. However, the mechanism by which this ...