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Updated: Jul 1, 2025

A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1
Xiaohang Yang1,2,3, Xingyuan Hu1,2, Jingjing Yin1,2
1Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, PR China.
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.
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