Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low dose treatment of high-grade serous ovarian carcinoma

Abstract

AbstractOvarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially, when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low dose approach utilising joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. In the present study, we found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and ovarian organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted activation of CDK1 by decreasing the phosphorylation levels of T14 and Y15 residues. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. Finally, the multiple low dosing was well tolerated in mice. These findings suggest a new multiple low dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.