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Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK

Author

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  • Jieqiong Wang

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
    Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University)

  • Kewen Hu

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Jiawei Guo

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Feixiong Cheng

    (State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University
    Bioinformatics and Systems Medicine Laboratory, Vanderbilt University Medical Center)

  • Jing Lv

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Wenhao Jiang

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Weiqiang Lu

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Jinsong Liu

    (The University of Texas MD Anderson Cancer Center)

  • Xiufeng Pang

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University)

  • Mingyao Liu

    (Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University
    Institute of Biosciences and Technology, Texas A&M University Health Science Center)

Abstract

No effective targeted therapies exist for cancers with somatic KRAS mutations. Here we develop a synthetic lethal chemical screen in isogenic KRAS-mutant and wild-type cells to identify clinical drug pairs. Our results show that dual inhibition of polo-like kinase 1 and RhoA/Rho kinase (ROCK) leads to the synergistic effects in KRAS-mutant cancers. Microarray analysis reveals that this combinatory inhibition significantly increases transcription and activity of cyclin-dependent kinase inhibitor p21WAF1/CIP1, leading to specific G2/M phase blockade in KRAS-mutant cells. Overexpression of p21WAF1/CIP1, either by cDNA transfection or clinical drugs, preferentially impairs the growth of KRAS-mutant cells, suggesting a druggable synthetic lethal interaction between KRAS and p21WAF1/CIP1. Co-administration of BI-2536 and fasudil either in the LSL-KRASG12D mouse model or in a patient tumour explant mouse model of KRAS-mutant lung cancer suppresses tumour growth and significantly prolongs mouse survival, suggesting a strong synergy in vivo and a potential avenue for therapeutic treatment of KRAS-mutant cancers.

Suggested Citation

  • Jieqiong Wang & Kewen Hu & Jiawei Guo & Feixiong Cheng & Jing Lv & Wenhao Jiang & Weiqiang Lu & Jinsong Liu & Xiufeng Pang & Mingyao Liu, 2016. "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11363
    DOI: 10.1038/ncomms11363
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