Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246-Sensitive Disease Subtype

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Identifying ovarian cancer patient subpopulations sensitive to targeted therapies is crucial for clinical benefit.
• Approximately 22% of high-grade ovarian cancer tumors exhibit low CIP2A oncoprotein expression at diagnosis.
• Some relapsed ovarian tumors maintain a CIP2A-deficient phenotype despite lower relapse likelihood after chemotherapy.

Purpose of the Study:

• To screen for therapeutics that selectively eliminate CIP2A-deficient ovarian cancer cells.
• To investigate the therapeutic potential of APR-246 in CIP2A-deficient ovarian cancer.
• To elucidate the mechanism underlying APR-246 hypersensitivity in CIP2A-deficient cells.

Main Methods:

• Drug screening to identify agents targeting CIP2A-deficient ovarian cancer cells.
• In vitro and in vivo testing of APR-246 in CIP2A-null mouse ovarian cancer models.
• Mechanistic studies involving NF-κB pathway analysis.

Main Results:

• APR-246, a reactive oxygen species inducer, was identified as a potent agent against CIP2A-deficient ovarian cancer cells.
• CIP2A-null ovarian cancer cells demonstrated hypersensitivity to APR-246 both in vitro and in vivo.
• Lack of CIP2A expression sensitizes cells to APR-246 via NF-κB pathway inhibition.
• Combination therapy with APR-246 and NF-κB inhibitors showed synergistic killing of CIP2A-positive ovarian cancer cells.

Conclusions:

• APR-246 warrants clinical investigation for patients with the CIP2A-deficient ovarian cancer subtype.
• CIP2A is a potential target for combination therapy with APR-246 in ovarian cancer treatment.
• These findings highlight a specific patient population that may benefit from APR-246 therapy.