Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246-Sensitive Disease Subtype.
Journal
Molecular cancer therapeutics
ISSN: 1538-8514
Titre abrégé: Mol Cancer Ther
Pays: United States
ID NLM: 101132535
Informations de publication
Date de publication:
05 07 2022
05 07 2022
Historique:
received:
19
07
2021
revised:
10
01
2022
accepted:
23
03
2022
pubmed:
2
4
2022
medline:
8
7
2022
entrez:
1
4
2022
Statut:
ppublish
Résumé
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag-driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
Identifiants
pubmed: 35364610
pii: 694123
doi: 10.1158/1535-7163.MCT-21-0622
pmc: PMC9256766
mid: NIHMS1795684
doi:
Substances chimiques
Autoantigens
0
NF-kappa B
0
Quinuclidines
0
eprenetapopt
Z41TGB4080
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1236-1245Subventions
Organisme : NCI NIH HHS
ID : P30 CA006927
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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