ATR inhibition overcomes platinum tolerance associated with ERCC1- and p53-deficiency by inducing replication catastrophe.
Journal
NAR cancer
ISSN: 2632-8674
Titre abrégé: NAR Cancer
Pays: England
ID NLM: 101769553
Informations de publication
Date de publication:
Mar 2023
Mar 2023
Historique:
received:
09
08
2021
revised:
30
11
2022
accepted:
16
12
2022
entrez:
16
1
2023
pubmed:
17
1
2023
medline:
17
1
2023
Statut:
epublish
Résumé
ERCC1/XPF is a heterodimeric DNA endonuclease critical for repair of certain chemotherapeutic agents. We recently identified that ERCC1- and p53-deficient lung cancer cells are tolerant to platinum-based chemotherapy. ATR inhibition synergistically re-stored platinum sensitivity to platinum tolerant ERCC1-deficient cells. Mechanistically we show this effect is reliant upon several functions of ATR including replication fork protection and altered cell cycle checkpoints. Utilizing an inhibitor of replication protein A (RPA), we further demonstrate that replication fork protection and RPA availability are critical for platinum-based drug tolerance. Dual treatment led to increased formation of DNA double strand breaks and was associated with chromosome pulverization. Combination treatment was also associated with increased micronuclei formation which were capable of being bound by the innate immunomodulatory factor, cGAS, suggesting that combination platinum and ATR inhibition may also enhance response to immunotherapy in ERCC1-deficient tumors.
Identifiants
pubmed: 36644397
doi: 10.1093/narcan/zcac045
pii: zcac045
pmc: PMC9832712
doi:
Types de publication
Journal Article
Langues
eng
Pagination
zcac045Subventions
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 : R01 CA229535
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009531
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Cancer.
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