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 4

ODF2L restrains CDK1 activity induced by AZD1775.

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ODF2L restrains CDK1 activity induced by AZD1775. (A) In vitro CDK1 acti...
(A) In vitro CDK1 activity (top2 plots) was analyzed in EOC cells with or without ODF2L knockdown and then treated with DMSO or AZD1775 (treatment: DMSO/200 nM AZD1775, 4 hours). (B) Immunoblots of the T14 and Y15 phosphorylation status of CDK1 in the indicated EOC cells (treatment: DMSO/200 nM AZD1775, 24 hours). (C and D) In vitro CDK1 activity (top 2 plots) was analyzed in CDK1 T14A–expressing (C), CDK1 Y15F–expressing (D), and CDK1 WT–expressing (C and D) EOC cells with endogenous CDK1 removed (treatment: DMSO or 200 nM AZD1775 for 4 hours). (E and F) Representative images and quantification of colony formation (E) and apoptotic cell death (F) of EOC cells with or without ODF2L knockdown. Cells were treated with sublethal doses of AZD1775 (A2780, 200 nM; SKOV3, 200 nM) together with or without 5 μM Ro-3306 for 72 hours. Data are the mean ± SD from 3 technical replicates of each sample and are representative of 3 (A), 2 (B), and 3 (C–F) independent biological experiments. Blots shown were run in parallel, contemporaneously using the same cell lysate harvested from 1 representative experiment for each cell line in A–D. ***P < 0.001 and ****P < 0.0001, by 1-way ANOVA.