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

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) a...

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Bibliographic Details
Published in:	Nature communications Vol. 10; no. 1; pp. 3476 - 14
Main Authors:	Cheng, Feixiong, Lu, Weiqiang, Liu, Chuang, Fang, Jiansong, Hou, Yuan, Handy, Diane E., Wang, Ruisheng, Zhao, Yuzheng, Yang, Yi, Huang, Jin, Hill, David E., Vidal, Marc, Eng, Charis, Loscalzo, Joseph
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02.08.2019 Nature Publishing Group Nature Portfolio
Subjects:	45 45/23 45/91 49/98 631/154 631/208 631/553 82/47 Adenocarcinoma Adenocarcinoma of Lung - drug therapy Adenocarcinoma of Lung - genetics Algorithms Anticancer properties Arrhythmia Arrhythmias, Cardiac - drug therapy Arrhythmias, Cardiac - genetics Cancer Computer Simulation Congestive heart failure Datasets as Topic Deoxyribonucleic acid Disease DNA DNA sequencing Drug Repositioning - methods Drugs Feasibility Studies Gene expression Gene Regulatory Networks - drug effects Genomes Heart Heart Failure - drug therapy Heart Failure - genetics Holistic Health Humanities and Social Sciences Humans Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lungs Metabolic Networks and Pathways - drug effects Metabolic Networks and Pathways - genetics Modules Molecular Targeted Therapy - methods multidisciplinary Ouabain Ouabain - pharmacology Ouabain - therapeutic use Protein Interaction Maps - drug effects Protein Interaction Maps - genetics Proteins Ribonucleic acid RNA Science Science (multidisciplinary) Systems Biology - methods Target recognition Transcription Factors - metabolism Transcriptome
ISSN:	2041-1723, 2041-1723
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Summary:	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. Identification of disease modules in the human interactome can guide more efficacious therapeutic selections. Here, the authors introduce a network-based methodology to identify individualized disease modules by mapping patients’ DNA and RNA sequencing profiles to the interactome, enabling prediction of cancer type-specific drug responses.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-10744-6