Identifying and targeting cancer-specific metabolism with network-based drug target prediction

EBioMedicine. 2019 May;43:98-106. doi: 10.1016/j.ebiom.2019.04.046. Epub 2019 May 22.

Abstract

Background: Metabolic rewiring allows cancer cells to sustain high proliferation rates. Thus, targeting only the cancer-specific cellular metabolism will safeguard healthy tissues.

Methods: We developed the very efficient FASTCORMICS RNA-seq workflow (rFASTCORMICS) to build 10,005 high-resolution metabolic models from the TCGA dataset to capture metabolic rewiring strategies in cancer cells. Colorectal cancer (CRC) was used as a test case for a repurposing workflow based on rFASTCORMICS.

Findings: Alternative pathways that are not required for proliferation or survival tend to be shut down and, therefore, tumours display cancer-specific essential genes that are significantly enriched for known drug targets. We identified naftifine, ketoconazole, and mimosine as new potential CRC drugs, which were experimentally validated.

Interpretation: The here presented rFASTCORMICS workflow successfully reconstructs a metabolic model based on RNA-seq data and successfully predicted drug targets and drugs not yet indicted for colorectal cancer. FUND: This study was supported by the University of Luxembourg (IRP grant scheme; R-AGR-0755-12), the Luxembourg National Research Fund (FNR PRIDE PRIDE15/10675146/CANBIO), the Fondation Cancer (Luxembourg), the European Union's Horizon2020 research and innovation programme under the Marie Sklodowska- Curie grant agreement No 642295 (MEL-PLEX), and the German Federal Ministry of Education and Research (BMBF) within the project MelanomSensitivity (BMBF/BM/7643621).

Keywords: Cancer; Drug repurposing; Machine learning; Metabolic modelling.

MeSH terms

  • Algorithms
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor*
  • Computational Biology* / methods
  • Drug Discovery* / methods
  • Energy Metabolism / drug effects*
  • Gene Deletion
  • Gene Expression Profiling
  • Humans
  • Molecular Targeted Therapy*
  • Reproducibility of Results
  • Workflow

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor