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

Nat Commun. 2019 Aug 2;10(1):3476. doi: 10.1038/s41467-019-10744-6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adenocarcinoma of Lung / drug therapy
  • Adenocarcinoma of Lung / genetics
  • Algorithms*
  • Arrhythmias, Cardiac / drug therapy
  • Arrhythmias, Cardiac / genetics
  • Computer Simulation
  • Datasets as Topic
  • Drug Repositioning / methods*
  • Feasibility Studies
  • Gene Regulatory Networks / drug effects
  • Heart Failure / drug therapy
  • Heart Failure / genetics
  • Holistic Health
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Metabolic Networks and Pathways / drug effects
  • Metabolic Networks and Pathways / genetics
  • Molecular Targeted Therapy / methods
  • Ouabain / pharmacology
  • Ouabain / therapeutic use
  • Protein Interaction Maps / drug effects
  • Protein Interaction Maps / genetics
  • Systems Biology / methods*
  • Transcription Factors / metabolism
  • Transcriptome


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • LEO1 protein, human
  • Transcription Factors
  • Ouabain