RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses.
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Date
2017-09-26ICR Author
Author
Dolly, SO
Gurden, MD
Drosopoulos, K
Clarke, P
de Bono, J
Kaye, S
Workman, P
Linardopoulos, S
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Subject
Cell Line, Tumor
Humans
Neoplasms
Sulfonamides
Ubiquitin-Protein Ligases
Protein-Serine-Threonine Kinases
Intracellular Signaling Peptides and Proteins
F-Box Proteins
Cell Cycle Proteins
Clathrin
RNA, Small Interfering
Cell Cycle
Mitosis
Apoptosis
RNA Interference
Thiazolidines
Synthetic Lethal Mutations
F-Box-WD Repeat-Containing Protein 7
Research team
Drug Target Discovery
Signal Transduction & Molecular Pharmacology
Prostate Cancer Targeted Therapy Group
Medicine Drug Development Unit (Kaye)
Language
eng
Date accepted
2017-07-24
License start date
2017-09
Citation
British journal of cancer, 2017, 117 (7), pp. 954 - 964
Publisher
NATURE PUBLISHING GROUP
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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