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

Gruet, M.; Xu, Y.; An, L.; Ma, Y.; Balcells, C.; Tyson, K.; Spear, S.; McKinney, F.; Babuta, J.; Bray, C.; Wickremesinghe, C.; Siskos, A. P.; Nijhuis, A. M.; Tate, E. W.; McNeish, I. A.; Benito, A.; Keun, H. C.

doi:10.1101/2024.10.15.618473

bioRxiv · 10.1101/2024.10.15.618473

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

Gruet, M.·Xu, Y.·An, L.·Ma, Y.·Balcells, C.·Tyson, K.·Spear, S.·McKinney, F.·Babuta, J.·Bray, C.·Wickremesinghe, C.·Siskos, A. P.·Nijhuis, A. M.·Tate, E. W.·McNeish, I. A.·Benito, A.·Keun, H. C.

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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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Gruet, M., Xu, Y., An, L., Ma, Y., Balcells, C., Tyson, K., Spear, S., McKinney, F., Babuta, J., Bray, C., Wickremesinghe, C., Siskos, A. P., Nijhuis, A. M., Tate, E. W., McNeish, I. A., Benito, A., Keun, H. C.. 2024-10-18. RAS/PI3K pathway mutations sensitise epithelial ovarian cancer cells to a PARP/NAMPT inhibitor combination. https://doi.org/10.1101/2024.10.15.618473

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