Introduction: High-grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian cancer. Despite therapeutic advances, most patients relapse, indicating the need for new treatments. PARP inhibitors (PARPi) have shown promise, particularly for patients with specific genetic mutations, but resistance remains a challenge. We have previously shown that NAMPT inhibitors (NAMPTi) can sensitize PARPi-resistant cells. In parallel, we have demonstrated that PARPi induces a reversible senescence state, which can be targeted with senolytics, creating a one-two punch strategy that is presently being tested in a phase I clinical trial (NTC05358639). Here we hypothesize that the new NAMPT-PARPi combination will trigger cell fate decisions, and in particular senescence, in NAMPT-PARPi treated HGSOC cells that can be further synergized by senolytics. 

Methods: We will investigate pathway alterations in transcriptome data from our cell line panel. We are also using the isogenic HGSOC cell lines to investigate the cellular outcomes when treated with NAMPTi-PARPi using live imaging and biomarker analysis to evaluate cell fate decisions that contribute to response.

Results: Based on our transcriptome analysis to date we have identified key pathways disrupted following treatment linked to different cell fate decisions, including senescence. We have shown that NAMPTi increases the sensitivity of PARPi in HGSOC-resistant cells both in vivo and in vitro and leads to significant DNA damage.

Conclusion: Our transcriptomic analysis indicates the disruption of senescence-associated pathways in response to PARPi, and we are currently investigating the use of senolytics and their potential contribution to enhancing the NAMPT-PARPi combination therapy. This "one-two-three-punch" approach additionally targets the metabolic adaptations utilized by cancer cells to evade therapy, providing an innovative way to overcome PARPi resistance in ovarian cancer.