ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models
Jie Li, … , Shuzhong Yao, Chaoyun Pan
Jie Li, … , Shuzhong Yao, Chaoyun Pan
Published November 15, 2022
Citation Information: J Clin Invest. 2023;133(2):e161544. https://doi.org/10.1172/JCI161544.
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Research Article Oncology

ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models

Abstract

WEE1 has emerged as an attractive target in epithelial ovarian cancer (EOC), but how EOC cells may alter their sensitivity to WEE1 inhibition remains unclear. Here, through a cell cycle machinery–related gene RNAi screen, we found that targeting outer dense fiber of sperm tails 2–like (ODF2L) was a synthetic lethal partner with WEE1 kinase inhibition in EOC cells. Knockdown of ODF2L robustly sensitized cells to treatment with the WEE1 inhibitor AZD1775 in EOC cell lines in vitro as well as in 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 levels, and sensitivity to WEE1 inhibition in patient-derived EOC cells. Moreover, ODF2L levels predicted the response to WEE1 inhibition in an EOC patient–derived xenograft model. Combination treatment with tumor-targeted lipid nanoparticles that packaged 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 EOC cells expressing low levels of ODF2L.

Authors

Jie Li, Jingyi Lu, Manman Xu, Shiyu Yang, Tiantian Yu, Cuimiao Zheng, Xi Huang, Yuwen Pan, Yangyang Chen, Junming Long, Chunyu Zhang, Hua Huang, Qingyuan Dai, Bo Li, Wei Wang, Shuzhong Yao, Chaoyun Pan

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Figure 6

ODF2L expression levels are clinically relevant to AZD1775 sensitivity in EOC.

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ODF2L expression levels are clinically relevant to AZD1775 sensitivity i...
(A and B) In vitro CDK1 activity, total ODF2L expression levels (A) and cell viability (B) were analyzed in AZD1775-treated EOC cells derived from the primary tumor tissue of 57 ovarian cancer patients. Patient 1 was used as a control for different batches and labeled blue. (C and D) Analysis of correlations between ODF2L expression levels and CDK1 activity (C) or cell viability (D) in AZD1775-treated primary EOC cells. ODF2L expression levels and CDK1 activity were measured by quantification of the blots in A using ImageJ software. (E) Effect of ODF2L expression levels on in vivo tumor growth of PDXs treated with AZD1775. Tumor tissue from patients 1, 5, and 10; patients 3 and 21; and patients 33 and 36 were chosen for the xenograft on the basis of the differential expression levels of ODF2L in the primary cells confirmed by Western blotting. Mice were evenly grouped when the volume of their tumors reached approximately 100 mm3 25 days after xenografting and were treated with vehicle or AZD1775 (40 mg/kg, orally, once per day). ID, identification. Data are representative of 2 (A) and 3 (B) independent biological experiments and represent the mean ± SD of 3 technical replicates of each sample (B). Error bars in E represent the SEM for tumor volume (n = 6). **P < 0.01 and ***P < 0.0001, by 2-tailed Pearson’s correlation coefficient (C and D), 2-way ANOVA for tumor volume (E), and 1-way ANOVA for tumor weight (F).