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

• Published in: Journal of biomedical informatics 2009-04, Vol.42 (2), p.228-236
• Main Authors: Durmus Tekir, S, Yalcin Arga, K, Ulgen, KO
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Drug Delivery Systems; Drug Discovery; Drug target; Epidermal growth factor receptor; Graph theory; Humans; Neoplasm Proteins - metabolism; Neoplasms - drug therapy; Neoplasms - metabolism; Network decomposition analysis; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction; Tumorigenesis
• ISSN: 1532-0464; 1532-0480
• DOI: 10.1016/j.jbi.2008.08.008

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 Gβ/Gγ 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.