Targeting ODF2L is synthetic lethal with WEE1 kinase inhibition in epithelial ovarian cancer models.

WEE1 has emerged as an attractive target in epithelial ovarian cancer (EOC), but how EOC cells may alter sensitivity to WEE1 inhibition remains unclear. Here, through a cell cycle machinery-related gene RNAi screen, we found that targeting ODF2L is synthetic lethal with WEE1 kinase inhibition in EOC cells. Knockdown of ODF2L robustly sensitized cells to treatment of the WEE1 inhibitor AZD1775 in EOC cell lines in vitro, as well as xenografts in vivo. Mechanistically, the increased sensitivity to WEE1 inhibition upon ODF2L loss was accompanied by accumulated DNA damage. ODF2L licensed the recruitment of PKMYT1, a functionally redundant kinase of WEE1, to the CDK1/cyclin B complex and thus restricted the activity of CDK1 when WEE1 was inhibited. Clinically, upregulation of ODF2L correlated with CDK1 activity, DNA damage level, and sensitivity to WEE1 inhibition in patient-derived EOC cells. Moreover, the ODF2L level predicted the response to WEE1 inhibition in an EOC patient-derived xenograft model. Combination treatment with tumor-targeted lipid nanoparticles that package ODF2L siRNA and AZD1775 led to the synergistic attenuation of tumor growth in the ID8 ovarian cancer syngeneic mouse model. These data suggest that WEE1 inhibition is a promising precision therapeutic strategy for ODF2L-low-expressing EOC cells.