RNAi screen reveals synthetic lethality between cyclin G-associated kinase and FBXW7 by inducing aberrant mitoses

Abstract

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.

TRIP13 promotes the cell proliferation, migration and invasion of glioblastoma through the FBXW7/c-MYC axis

“…Therefore, the stability of the c-MYC protein is strictly controlled by FBXW7, which is an E3 ubiquitin ligase involved in ubiquitination and degradation of various carcinogenic substrates that contain F-box and WD40 repeat domains. 24 Many studies have shown that abnormal expression of FBXW7 is the main cause of tumorigenesis. 25 – 27 Inactivation of FBXW7 expression will enhance the proliferation and migration of tumours.…”

A Scaffold‐Hopping Strategy toward the Identification of Inhibitors of Cyclin G Associated Kinase

“…It has been demonstrated that siRNA‐mediated GAK knockdown results in mitotic arrest during metaphase and multipolar spindle formation . Due to this mitotic involvement, GAK is a potential drug target for the treatment of BXW7‐deficient tumors, such as cholangiocarcinoma . GAK was also identified as a potential target for the inhibition of prostate cancer growth in cells expressing androgen receptor splice variants .…”

SGC-GAK-1: a chemical probe for cyclin G associated kinase (GAK)

“…To date all studies of the role of GAK in prostate cancer have utilized knock-down of the whole protein. 28 We now show for the first time that inhibition of the GAK kinase domain alone can block the growth of prostate cancer cells. Our results demonstrate that the kinase and not the auxilin-homology domain is critical for this phenotype in cells.…”