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

Xiaohang Yang, Xingyuan Hu, Jingjing Yin, Wenting Li, Yu Fu, Bin Yang, Junpeng Fan, Funian Lu, Tianyu Qin, Xiaoyan Kang, Xucui Zhuang, Fuxia Li, Rourou Xiao, Tingyan Shi, Kun Song, Jing Li (), Gang Chen () and Chaoyang Sun ()
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Xiaohang Yang: Huazhong University of Science and Technology
Xingyuan Hu: Huazhong University of Science and Technology
Jingjing Yin: Huazhong University of Science and Technology
Wenting Li: Huazhong University of Science and Technology
Yu Fu: Huazhong University of Science and Technology
Bin Yang: Huazhong University of Science and Technology
Junpeng Fan: Huazhong University of Science and Technology
Funian Lu: Huazhong University of Science and Technology
Tianyu Qin: Huazhong University of Science and Technology
Xiaoyan Kang: Huazhong University of Science and Technology
Xucui Zhuang: Huazhong University of Science and Technology
Fuxia Li: The First Affiliated Hospital of Shihezi University Shihezi
Rourou Xiao: Zhongnan Hospital of Wuhan University
Tingyan Shi: Fudan University
Kun Song: Qilu Hospital of Shandong University
Jing Li: Sun Yat-sen Memorial Hospital
Gang Chen: Huazhong University of Science and Technology
Chaoyang Sun: Huazhong University of Science and Technology

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46358-w

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