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

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 Lobe 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. (C) 2019 The Authors. Published by Elsevier B.V.