ONC201 in combination with ATR inhibitor ceralasertib exhibits potent synergy in ovarian cancer cells

Ovarian cancer remains a highly lethal gynecological cancer in the United States. While patients often respond well to treatment, it commonly returns and develops resistance. This highlights the need to investigate novel combinations to improve survival rates. Preclinical studies have shown that both ATRi (Ataxia telangiectasia and Rad3-related inhibitors) and ONC201 can be effective in treating ovarian cancer.

Researchers hypothesized that combining these two could boost their combined efficacy. They tested this hypothesis using ONC201, which triggers apoptosis via the TRAIL-pathway by activating the integrated stress response and inhibiting Akt, which is elevated in ovarian cancer. Six human ovarian cancer cell lines were treated with either ONC201 or ceralasertib (an ATRi) alone or in combination.

The results showed that the combination of ONC201 and ceralasertib had an IC50 range of 0.88-20.16 microM, while ONC201 alone ranged from 0.88-20.16 microM, and ceralasertib alone ranged from 0.55-54.75 microM. The combined treatment led to PARP cleavage, indicative of apoptosis, and reduced expression of Bcl-XL, Xiap, and p-Akt after 72 hours.

Additionally, cytokine profiling revealed a decrease in inflammation markers and tumor progression. These findings suggest a synergistic effect between the ATRi ceralasertib and ONC201 in combating ovarian cancer cells, warranting further investigation and potential clinical translation.