A genome-wide positioning systems network algorithm for in silico drug repurposing

Feixiong Cheng, Weiqiang Lu, Chuang Liu, Jiansong Fang, Yuan Hou, Diane E. Handy, Ruisheng Wang, Yuzheng Zhao, Yi Yang, Jin Huang, David E. Hill, Marc Vidal, Charis Eng and Joseph Loscalzo ()
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Feixiong Cheng: Lerner Research Institute, Cleveland Clinic
Weiqiang Lu: East China Normal University
Chuang Liu: Hangzhou Normal University
Jiansong Fang: Lerner Research Institute, Cleveland Clinic
Yuan Hou: Lerner Research Institute, Cleveland Clinic
Diane E. Handy: Harvard Medical School
Ruisheng Wang: Harvard Medical School
Yuzheng Zhao: East China University of Science and Technology
Yi Yang: East China University of Science and Technology
Jin Huang: East China University of Science and Technology
David E. Hill: Dana-Farber Cancer Institute
Marc Vidal: Dana-Farber Cancer Institute
Charis Eng: Lerner Research Institute, Cleveland Clinic
Joseph Loscalzo: Harvard Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Recent advances in DNA/RNA sequencing have made it possible to identify new targets rapidly and to repurpose approved drugs for treating heterogeneous diseases by the ‘precise’ targeting of individualized disease modules. In this study, we develop a Genome-wide Positioning Systems network (GPSnet) algorithm for drug repurposing by specifically targeting disease modules derived from individual patient’s DNA and RNA sequencing profiles mapped to the human protein-protein interactome network. We investigate whole-exome sequencing and transcriptome profiles from ~5,000 patients across 15 cancer types from The Cancer Genome Atlas. We show that GPSnet-predicted disease modules can predict drug responses and prioritize new indications for 140 approved drugs. Importantly, we experimentally validate that an approved cardiac arrhythmia and heart failure drug, ouabain, shows potential antitumor activities in lung adenocarcinoma by uniquely targeting a HIF1α/LEO1-mediated cell metabolism pathway. In summary, GPSnet offers a network-based, in silico drug repurposing framework for more efficacious therapeutic selections.

Date: 2019
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DOI: 10.1038/s41467-019-10744-6

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