125P - Combination of navitoclax with alpelisib and trametinib to synergistically impair cell viability in high-grade ovarian cancer

Background

High-grade serous ovarian cancer (HGSOC) is the most lethal histologic subtype of ovarian cancer and even though therapies have improved significantly over the last years, survival rates remain low. Thus, improvements for treating patients suffering from this disease are urgently needed.¹ Combination of already available drugs aims to enhance treatment response in cancer patients by employing their synergistic interactions.² This project aimed to investigate effects of a combined targeting of cell proliferation and apoptosis in HGSOC.

Methods

Four HGSOC cell lines were exposed to the PIK3CA inhibitor alpelisib, pan-MEK inhibitor trametinib and BH3-mimetic navitoclax at 10, 5, 2.5 and 1.25 μM each. Alpelisib and trametinib were each combined with navitoclax. Cells were seeded in 96 well plates and left to attach to the surface for 24 h before drug exposure. Viability was assessed after 72 h using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega). Experiments were repeated independently three times and analyses were performed in R. Findings were evaluated as significant if p ≤ 0.05.

Results

Taken together initial outcomes indicate synergistic interactions of navitoclax with alpelisib and trametinib. Drug combinations enhanced inhibition of cell viability when compared to single agent treatment. Overall, navitoclax and trametinib impaired viability more than the combination of navitoclax with alpelisib, resulting in a higher combination sensitivity score (CSS). Even though no combination statistically outperformed treatment with 10 μM navitoclax, combinations significantly reduced viability when compared to the highest concentration of alpelisib and trametinib. The lowest concentration to significantly reduce viability in combination screens was 5 μM of each drug.

Conclusions

These first results confirm that targeting proliferation and apoptosis synergistically impair cell viability in HGSOC and might therefore be interesting targets to induce synthetic lethality. Based on these screening results further investigations will focus on induction of apoptosis and the underlying molecular mechanisms. Furthermore, these results will be validated in a 3D model using HGSOC organoids.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

L. Wozelka-Oltjan.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.