RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination
File(s)
Published version
Author(s)
Keun, Hector
Type
Journal Article
Abstract
The combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of TNBC, Ewing Sarcoma and high grade serous carcinoma (HGSC). However, dose limiting toxicity has hampered NAMPTi in clinical trials. To maximise the therapeutic window, we set out to identify predictive genomic biomarkers. Bioinformatic analysis and screening of a panel of epithelial ovarian cancer (EOC) cell lines revealed that cells with RAS/PI3K pathway mutations were sensitive to the NAMPTi FK866. Combined exposure to olaparib and FK866 was associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD+ 21 ), with coincident increases in ROS production, DNA damage and
apoptosis induction. Caspase 3/7 activity was upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduced omental tumour weight and increased overall survival in mice injected
with ID8 Trp53-/-;Pten-/- 24 cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.
apoptosis induction. Caspase 3/7 activity was upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduced omental tumour weight and increased overall survival in mice injected
with ID8 Trp53-/-;Pten-/- 24 cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.
Date Issued
2026-01-03
Date Acceptance
2025-12-02
Citation
Communications Biology, 2026, 9
ISSN
2399-3642
Publisher
Nature Portfolio
Journal / Book Title
Communications Biology
Volume
9
Copyright Statement
Copyright This paper is embargoed until publication. Once published the Version of Record (VoR) will be available on immediate open access.
License URL
Identifier
10.1038/s42003-025-09223-0
Publication Status
Published
Article Number
6
Date Publish Online
2025-12-19