Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation

被引：5

作者：

Yang, Xiaohang ^{[1
,2
,3
]}

Hu, Xingyuan ^{[1
,2
]}

Yin, Jingjing ^{[1
,2
]}

Li, Wenting ^{[1
,2
,4
]}

Fu, Yu ^{[1
,2
]}

Yang, Bin ^{[1
,2
]}

Fan, Junpeng ^{[1
,2
]}

Lu, Funian ^{[1
,2
]}

Qin, Tianyu ^{[1
,2
]}

Kang, Xiaoyan ^{[1
,2
]}

Zhuang, Xucui ^{[1
,2
]}

Li, Fuxia ^{[4
]}

Xiao, Rourou ^{[5
]}

Shi, Tingyan ^{[6
]}

Song, Kun ^{[3
]}

Li, Jing ^{[7
]}

Chen, Gang ^{[1
,2
]}

Sun, Chaoyang ^{[1
,2
]}

机构：

[1] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Canc Biol Res Ctr,Key Lab Minist Educ, Wuhan 430000, Hubei, Peoples R China

[2] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Gynecol & Obstet, Tongji Med Coll, Wuhan 430000, Hubei, Peoples R China

[3] Shandong Univ, Dept Obstet & Gynecol, Qilu Hosp, Jinan 250012, Peoples R China

[4] Shihezi Univ Shihezi, Dept Obstet & Gynecol, Affiliated Hosp 1, Xinjiang 832000, Peoples R China

[5] Wuhan Univ, Dept Gynecol & Obstet, Zhongnan Hosp, Wuhan 430071, Hubei, Peoples R China

[6] Fudan Univ, Zhongshan Hosp, Dept Gynecol Oncol, Ovarian Canc Program, Shanghai 200032, Peoples R China

[7] Sun Yat Sen Mem Hosp, Dept Gynecol Oncol, 33 Yingfeng Rd, Guangzhou 510000, Peoples R China

来源：

NATURE COMMUNICATIONS | 2024年 / 15卷 / 01期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

CYCLIN-DEPENDENT KINASES; INTRAPERITONEAL CHEMOTHERAPY; CELL-CYCLE; REPLICATION CATASTROPHE; MILD HYPERTHERMIA; GENOME INTEGRITY; OVARIAN-CANCER; PHOSPHORYLATION; TRANSCRIPTION; PHOSPHATASES;

D O I：

10.1038/s41467-024-46358-w

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Hyperthermic intraperitoneal chemotherapy's role in ovarian cancer remains controversial, hindered by limited understanding of hyperthermia-induced tumor cellular changes. This limits developing potent combinatory strategies anchored in hyperthermic intraperitoneal therapy (HIPET). Here, we perform a comprehensive multi-omics study on ovarian cancer cells under hyperthermia, unveiling a distinct molecular panorama, primarily characterized by rapid protein phosphorylation changes. Based on the phospho-signature, we pinpoint CDK1 kinase is hyperactivated during hyperthermia, influencing the global signaling landscape. We observe dynamic, reversible CDK1 activity, causing replication arrest and early mitotic entry post-hyperthermia. Subsequent drug screening shows WEE1 inhibition synergistically destroys cancer cells with hyperthermia. An in-house developed miniaturized device confirms hyperthermia and WEE1 inhibitor combination significantly reduces tumors in vivo. These findings offer additional insights into HIPET, detailing molecular mechanisms of hyperthermia and identifying precise drug combinations for targeted treatment. This research propels the concept of precise hyperthermic intraperitoneal therapy, highlighting its potential against ovarian cancer.

引用

页数：23