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

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  • Xiaohang Yang

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    Qilu Hospital of Shandong University)

  • Xingyuan Hu

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Jingjing Yin

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Wenting Li

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology
    The First Affiliated Hospital of Shihezi University Shihezi)

  • Yu Fu

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Bin Yang

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Junpeng Fan

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Funian Lu

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Tianyu Qin

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Xiaoyan Kang

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

  • Xucui Zhuang

    (Huazhong University of Science and Technology
    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
    Huazhong University of Science and Technology)

  • Chaoyang Sun

    (Huazhong University of Science and Technology
    Huazhong University of Science and Technology)

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.

Suggested Citation

  • 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, 2024. "Comprehensive multi-omics analysis reveals WEE1 as a synergistic lethal target with hyperthermia through CDK1 super-activation," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46358-w
    DOI: 10.1038/s41467-024-46358-w
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    References listed on IDEAS

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    1. Silvia Domcke & Rileen Sinha & Douglas A. Levine & Chris Sander & Nikolaus Schultz, 2013. "Evaluating cell lines as tumour models by comparison of genomic profiles," Nature Communications, Nature, vol. 4(1), pages 1-10, October.
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