BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.
BH3-mimetics
Drug resistance
MDM2
RG7388
p53 mutation
Journal
Apoptosis : an international journal on programmed cell death
ISSN: 1573-675X
Titre abrégé: Apoptosis
Pays: Netherlands
ID NLM: 9712129
Informations de publication
Date de publication:
02 Sep 2024
02 Sep 2024
Historique:
accepted:
15
08
2024
medline:
2
9
2024
pubmed:
2
9
2024
entrez:
2
9
2024
Statut:
aheadofprint
Résumé
The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.
Identifiants
pubmed: 39222276
doi: 10.1007/s10495-024-02014-8
pii: 10.1007/s10495-024-02014-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : The Russian Science Foundation
ID : 23-74-30006
Organisme : The Russian Science Foundation
ID : 23-74-30006
Organisme : Cancerfonden
ID : 222013
Organisme : Cancerföreningen i Stockholm
ID : 181301
Informations de copyright
© 2024. The Author(s).
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