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A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds.

Cairney, CJ; Godwin, LS; Bilsland, AE; Burns, S; Stevenson, KH; McGarry, L; Revie, J; Moore, JD; Wiggins, CM; Collinson, RS; et al. Cairney, CJ; Godwin, LS; Bilsland, AE; Burns, S; Stevenson, KH; McGarry, L; Revie, J; Moore, JD; Wiggins, CM; Collinson, RS; Mudd, C; Tsonou, E; Sadaie, M; Bennett, DC; Narita, M; Torrance, CJ; Keith, WN (2017) A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds. PLoS Genet, 13 (8). ISSN 1553-7404 https://doi.org/10.1371/journal.pgen.1006942
SGUL Authors: Bennett, Dorothy Catherine

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Abstract

Senescence is a universal barrier to immortalisation and tumorigenesis. As such, interest in the use of senescence-induction in a therapeutic context has been gaining momentum in the past few years; however, senescence and immortalisation remain underserved areas for drug discovery owing to a lack of robust senescence inducing agents and an incomplete understanding of the signalling events underlying this complex process. In order to address this issue we undertook a large-scale morphological siRNA screen for inducers of senescence phenotypes in the human melanoma cell line A375P. Following rescreen and validation in a second cancer cell line, HCT116 colorectal carcinoma, a panel of 16 of the most robust hits were selected for further validation based on significance and the potential to be targeted by drug-like molecules. Using secondary assays for detection of senescence biomarkers p21, 53BP1 and senescence associated beta-galactosidase (SAβGal) in a panel of HCT116 cell lines carrying cancer-relevant mutations, we show that partial senescence phenotypes can be induced to varying degrees in a context dependent manner, even in the absence of p21 or p53 expression. However, proliferation arrest varied among genetic backgrounds with predominantly toxic effects in p21 null cells, while cells lacking PI3K mutation failed to arrest. Furthermore, we show that the oncogene ECT2 induces partial senescence phenotypes in all mutant backgrounds tested, demonstrating a dependence on activating KRASG13D for growth suppression and a complete senescence response. These results suggest a potential mechanism to target mutant KRAS signalling through ECT2 in cancers that are reliant on activating KRAS mutations and remain refractory to current treatments.

Item Type: Article
Additional Information: © 2017 Cairney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Developmental Biology, 0604 Genetics
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: PLoS Genet
Article Number: e1006942
ISSN: 1553-7404
Language: eng
Dates:
DateEvent
14 August 2017Published
25 July 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
C2193/A15584Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
C301/A12962Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
PubMed ID: 28806777
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/109090
Publisher's version: https://doi.org/10.1371/journal.pgen.1006942

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