ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models
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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-01-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI161544 |
| _version_ | 1797634483450544128 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jie Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:27Z |
| format | Article |
| id | doaj.art-1837d1b7a0194de9b0a40257fc4574c1 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:27Z |
| publishDate | 2023-01-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-1837d1b7a0194de9b0a40257fc4574c12023-11-07T16:19:47ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-01-011332ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer modelsJie LiJingyi LuManman XuShiyu YangTiantian YuCuimiao ZhengXi HuangYuwen PanYangyang ChenJunming LongChunyu ZhangHua HuangQingyuan DaiBo LiWei WangShuzhong YaoChaoyun PanWEE1 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.https://doi.org/10.1172/JCI161544Oncology |
| spellingShingle | 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 ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models The Journal of Clinical Investigation Oncology |
| title | ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models |
| title_full | ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models |
| title_fullStr | ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models |
| title_full_unstemmed | ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models |
| title_short | ODF2L acts as a synthetic lethal partner with WEE1 inhibition in epithelial ovarian cancer models |
| title_sort | odf2l acts as a synthetic lethal partner with wee1 inhibition in epithelial ovarian cancer models |
| topic | Oncology |
| url | https://doi.org/10.1172/JCI161544 |
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