A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis.
HDAC inhibitor
PARP inhibitor
chromothripsis
synergy
synthetic lethality
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
15 08 2022
15 08 2022
Historique:
revised:
15
12
2021
received:
19
07
2021
accepted:
25
01
2022
pubmed:
13
4
2022
medline:
18
6
2022
entrez:
12
4
2022
Statut:
ppublish
Résumé
Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
Substances chimiques
Hedgehog Proteins
0
Poly(ADP-ribose) Polymerase Inhibitors
0
DNA
9007-49-2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
590-606Informations de copyright
© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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