Alexandros P. Siskos

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

Abstract The combination of PARP and NAMPT inhibitors (PARPi/NAMPTi) has been explored for the treatment of triple-negative breast cancer, 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 are sensitive to the NAMPTi FK866. Combined exposure to olaparib and FK866 is 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 is upregulated to a greater extent in RAS/PI3K mutant cell lines. Finally, the combination significantly reduces omental tumour weight and increases 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.