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

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 per...

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Published inNature communications Vol. 15; no. 1; p. 2089
Main Authors Yang, Xiaohang, Hu, Xingyuan, Yin, Jingjing, Li, Wenting, Fu, Yu, Yang, Bin, Fan, Junpeng, Lu, Funian, Qin, Tianyu, Kang, Xiaoyan, Zhuang, Xucui, Li, Fuxia, Xiao, Rourou, Shi, Tingyan, Song, Kun, Li, Jing, Chen, Gang, Sun, Chaoyang
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 07.03.2024
Nature Portfolio
Subjects
Biological analysis
Cancer
Cancer therapies
CDC2 Protein Kinase - metabolism
Cell Cycle Proteins - metabolism
Chemotherapy
Drug screening
Female
Fever
Humans
Hyperthermia
Hyperthermia, Induced
Kinases
Mitosis
Molecular modelling
Multiomics
Ovarian cancer
Ovarian Neoplasms - pathology
Ovarian Neoplasms - therapy
Phosphorylation
Protein-Tyrosine Kinases - metabolism
Therapeutic targets
Tumors
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Summary: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.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-46358-w