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.
International Cancer Genome Consortium PedBrain Tumor ProjectPediatric 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 ...
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Mackay, A; Burford, A; Carvalho, D; Izquierdo, E; Fazal-Salom, J; Taylor, KR; Bjerke, L; Clarke, M; Vinci, M; Nandhabalan, M; Temelso, S; Popov, S; Molinari, V; Raman, P; Waanders, AJ; Han, HJ; Gupta, S; Marshall, L; Zacharoulis, S; Vaidya, S; Mandeville, HC; Bridges, LR; Martin, AJ; Al-Sarraj, S; Chandler, C; Ng, H-K; Li, X; Mu, K; Trabelsi, S; Brahim, DH-B; Kisljakov, AN; Konovalov, DM; Moore, AS; Carcaboso, AM; Sunol, M; de Torres, C; Cruz, O; Mora, J; Shats, LI; Stavale, JN; Bidinotto, LT; Reis, RM; Entz-Werle, N; Farrell, M; Cryan, J; Crimmins, D; Caird, J; Pears, J; Monje, M; Debily, M-A; Castel, D; Grill, J; Hawkins, C; Nikbakht, H; Jabado, N; Baker, SJ; Pfister, SM; Jones, DTW; Fouladi, M; von Bueren, AO; Baudis, M; Resnick, A; Jones, C (2017-10-09)We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating ...
TGFβ-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells. Suresh Babu, S; Valdez, Y; Xu, A; O'Byrne, AM; Calvo, F; Lei, V; Conway, EM (2014-01)BACKGROUND: CD248 is a cell surface glycoprotein, highly expressed by stromal cells and fibroblasts of tumors and inflammatory lesions, but virtually undetectable in healthy adult tissues. CD248 promotes tumorigenesis, ...