Drug targets for tumorigenesis: insights from structural analysis of EGFR signaling network

J Biomed Inform. 2009 Apr;42(2):228-36. doi: 10.1016/j.jbi.2008.08.008. Epub 2008 Aug 26.

Abstract

Deciphering the complex network structure is crucial in drug target identification. This study presents a framework incorporating graph theoretic and network decomposition methods to analyze system-level properties of the comprehensive map of the epidermal growth factor receptor (EGFR) signaling, which is a good candidate model system to study the general mechanisms of signal transduction. The graph theoretic analysis of the EGFR network indicates that it has small-world characteristics with scale-free topology. The employment of network decomposition analysis enlightened the system-level properties, such as network cross-talk, specific molecules in each pathway and participation of molecules in the network. Participating in a significant fraction of the fundamental paths connecting the ligands to the phenotypes, cofactor GTP and complex Gbeta/Ggamma were identified as "housekeeping" molecules, through which all pathways of EGFR network are cross-talking. c-Src-Shc complex is identified as important due to its role in all fundamental paths through tumorigenesis and being specific to this phenotype. Inhibitors of this complex may be good anti-cancer agents having very little or no effect on other phenotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Drug Delivery Systems
  • Drug Discovery*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Humans
  • Neoplasm Proteins / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Signal Transduction*

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • ErbB Receptors