Pharmacological Inhibition of ATR Can Block Autophagy through an ATR-Independent Mechanism.
Biochemical Mechanism
Biochemistry
Biological Sciences
Cancer
Journal
iScience
ISSN: 2589-0042
Titre abrégé: iScience
Pays: United States
ID NLM: 101724038
Informations de publication
Date de publication:
20 Nov 2020
20 Nov 2020
Historique:
received:
02
08
2020
revised:
25
09
2020
accepted:
07
10
2020
entrez:
2
11
2020
pubmed:
3
11
2020
medline:
3
11
2020
Statut:
epublish
Résumé
Inhibition of the ATR kinase has emerged as a therapeutically attractive means to target cancer since the development of potent inhibitors, which are now in clinical testing. We investigated a potential link between ATR inhibition and the autophagy process in esophageal cancer cells using four ATR inhibitors including two in clinical testing. The response to pharmacological ATR inhibitors was compared with genetic systems to investigate the ATR dependence of the effects observed. The ATR inhibitor, VX-970, was found to lead to an accumulation of p62 and LC3-II indicative of a blocked autophagy. This increase in p62 occurred post-transcriptionally and in all the cell lines tested. However, our data indicate that the accumulation of p62 occurred in an ATR-independent manner and was instead an off-target response to the ATR inhibitor. This study has important implications for the clinical response to pharmacological ATR inhibition, which in some cases includes the blockage of autophagy.
Identifiants
pubmed: 33134898
doi: 10.1016/j.isci.2020.101668
pii: S2589-0042(20)30860-9
pmc: PMC7588853
doi:
Types de publication
Journal Article
Langues
eng
Pagination
101668Subventions
Organisme : Medical Research Council
ID : MR/N009460/1
Pays : United Kingdom
Informations de copyright
© 2020 The Author(s).
Déclaration de conflit d'intérêts
The authors declare no competing interests.
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