RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination

Michael Gruet; Yitao Xu; Lijie An; Yurui Ma; Cristina Domingo Balcells; Katie Tyson; Laila C. Evangelista; Sarah Spear; Yuewei Xu; Flora McKinney; Julia Babuta; Chandler Bray; Chiharu Wickremesinghe; Alexandros Siskos; Anke M. Nijhuis; Edward W. Tate; Iain A. McNeish; Adrián Benito; Hector C. Keun

doi:10.1038/s42003-025-09223-0

Cancer BiologyCommunications BiologyDec 19, 2025

Peer-reviewed journal article

RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination

Michael Gruet iD, Yitao Xu iD, Lijie An iD, Yurui Ma iD, Cristina Domingo Balcells iD, Katie Tyson iD, Laila C. Evangelista iD, Sarah Spear iD, Yuewei Xu iD, Flora McKinney iD, Julia Babuta iD, Chandler Bray, Chiharu Wickremesinghe iD, Alexandros Siskos iD, Anke M. Nijhuis iD, Edward W. Tate iD, Iain A. McNeish iD, Adrián Benito iD, Hector C. Keun iD

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. Activity of olaparib and FK866 was associated with a reduction in nicotinamide mononucleotide (NMN) and the PARP substrate nicotinamide adenine dinucleotide (NAD+), 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-/- cells. This study highlights the potential of the PARPi/NAMPTi combination in RAS/PI3K pathway mutant EOC.

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