Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
received:
16
10
2018
accepted:
22
07
2020
entrez:
19
8
2020
pubmed:
19
8
2020
medline:
9
9
2020
Statut:
epublish
Résumé
In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.
Identifiants
pubmed: 32807787
doi: 10.1038/s41467-020-17958-z
pii: 10.1038/s41467-020-17958-z
pmc: PMC7431578
doi:
Substances chimiques
RNA, Small Interfering
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
4124Subventions
Organisme : NCI NIH HHS
ID : R01 CA245314
Pays : United States
Organisme : NIA NIH HHS
ID : K99 AG045144
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : NIBIB NIH HHS
ID : F32 EB017614
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES028374
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM104047
Pays : United States
Organisme : NIA NIH HHS
ID : R00 AG045144
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA226898
Pays : United States
Organisme : NIEHS NIH HHS
ID : R01 ES015339
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA034992
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA034992
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211184
Pays : United States
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