RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses.
de Bono, J
MetadataShow full item record
BACKGROUND: 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. METHODS: We performed a siRNA kinome screen to identify synthetically lethal hits to FBXW7 deficiency. RESULTS: 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. CONCLUSIONS: 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 Cycle Proteins
Cell Line, Tumor
F-Box-WD Repeat-Containing Protein 7
Intracellular Signaling Peptides and Proteins
RNA, Small Interfering
Synthetic Lethal Mutations
Drug Target Discovery
Signal Transduction & Molecular Pharmacology
Prostate Cancer Targeted Therapy Group
License start date
Br J 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.
Mardakheh, FK; Self, A; Marshall, CJ (2016-12-15)Directional cell migration involves reorientation of the secretory machinery. However, the molecular mechanisms that control this reorientation are not well characterised. Here, we identify a new Rho effector protein, named ...
Ecdysone-inducible expression of oncogenic Ha-Ras in NIH 3T3 cells leads to transient nuclear localization of activated extracellular signal-regulated kinase regulated by mitogen-activated protein kinase phosphatase-1. Plows, D; Briassouli, P; Owen, C; Zoumpourlis, V; Garrett, MD; Pintzas, A (2002-03)The Ras family of GTP-binding proteins are key transducers of extracellular signals, particularly through the mitogen-activated protein kinase (MAPK) pathway. Constitutively active forms of Ras are found in a variety of ...
International Cancer Genome Consortium PedBrain Tumor Project (2016-11)Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously ...