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

Cairney, C. J. et al. (2017) A 'synthetic-sickness' screen for senescence re-engagement targets in mutant cancer backgrounds. PLoS Genetics, 13(8), e1006942. (doi:10.1371/journal.pgen.1006942) (PMID:28806777) (PMCID:PMC5570495)

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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:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burns, Mrs Sharon and Cairney, Dr Claire and Keith, Professor Nicol and Bilsland, Dr Alan and Stevenson, Mrs Katrina
Authors: Cairney, C. J., Godwin, L. S., Bilsland, A. E., Burns, S., Stevenson, K. H., McGarry, L., Revie, J., Moore, J. D., Wiggins, C. M., Collinson, R. S., Mudd, C., Tsonou, E., Sadaie, M., Bennett, D. C., Narita, M., Torrance, C. J., and Keith, W. N.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:PLoS Genetics
Publisher:Public Library of Science
ISSN:1553-7390
ISSN (Online):1553-7404
Copyright Holders:Copyright © 2017 Cairney et al.
First Published:First published in PLoS Genetics 13(8):e1006942
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
573449Experimental Cancer Medicine Centre (ECMC)Thomas EvansCancer Research UK (CRUK)15584ICS - EXPERIMENTAL THERAPEUTICS
551312Senectus: Exploitation of a Cell Senescence Drug Discovery ProgramNicol KeithCancer Research UK (CRUK)C301/A12962RI CANCER SCIENCES