Identification and Characterization of Synthetic Viability with ERCC1 Deficiency in Response to Interstrand Crosslinks in Lung Cancer.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 Apr 2019
15 Apr 2019
Historique:
received:
21
09
2018
revised:
14
11
2018
accepted:
06
12
2018
pubmed:
13
12
2018
medline:
4
7
2019
entrez:
13
12
2018
Statut:
ppublish
Résumé
ERCC1/XPF is a DNA endonuclease with variable expression in primary tumor specimens, and has been investigated as a predictive biomarker for efficacy of platinum-based chemotherapy. The failure of clinical trials utilizing ERCC1 expression to predict response to platinum-based chemotherapy suggests additional mechanisms underlying the basic biology of ERCC1 in the response to interstrand crosslinks (ICLs) remain unknown. We aimed to characterize a panel of ERCC1 knockout (Δ) cell lines, where we identified a synthetic viable phenotype in response to ICLs with ERCC1 deficiency. We utilized the CRISPR-Cas9 system to create a panel of ERCC1Δ lung cancer cell lines which we characterized. We observe that loss of ERCC1 hypersensitizes cells to cisplatin when wild-type (WT) p53 is retained, whereas there is only modest sensitivity in cell lines that are p53 Our findings implicate p53 as a potential confounding variable in clinical assessments of ERCC1 as a platinum biomarker via promoting an environment in which error-prone mechanisms of ICL-R may be able to partially compensate for loss of ERCC1.
Identifiants
pubmed: 30538112
pii: 1078-0432.CCR-18-3094
doi: 10.1158/1078-0432.CCR-18-3094
pmc: PMC6467763
mid: NIHMS1516670
doi:
Substances chimiques
DNA-Binding Proteins
0
ERCC1 protein, human
EC 3.1.-
Endonucleases
EC 3.1.-
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2523-2536Subventions
Organisme : NCI NIH HHS
ID : P30 CA022453
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA141769
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009531
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
©2018 American Association for Cancer Research.
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