Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy

• Published in: Current cancer drug targets Vol. 9; no. 6; p. 748
• Main Authors: van der Veeken, J, Oliveira, S, Schiffelers, R M, Storm, G, van Bergen En Henegouwen, P M P, Roovers, R C
• Format: Journal Article
• Language: English
• Published: Netherlands 01-09-2009
• Subjects: Antineoplastic Agents - pharmacology; Drug Delivery Systems; Drug Discovery; Enzyme Activation; Humans; Models, Biological; Receptor Cross-Talk - drug effects; Receptor Cross-Talk - physiology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Signal Transduction - physiology
• ISSN: 1873-5576
• DOI: 10.2174/156800909789271495

Both the epidermal growth factor receptor (EGFR) and the insulin-like growth factor-1 receptor (IGF-1R) can contribute to tumor development and -progression through their effects on cell proliferation, inhibition of apoptosis, angiogenesis, anchorage-independent growth and tumor-associated inflammation. EGFR-targeting monoclonal antibodies and small molecule tyrosine kinase inhibitors are currently in clinical use for the treatment of several types of cancer. However, primary and acquired resistance to these agents often occurs and thereby limits the clinical efficacy of mono-specific targeted therapy. Results from both in vitro and in vivo studies indicate that cross-talk between EGFR and IGF-1R can lead to acquired resistance against EGFR-targeted drugs. This review describes the interface between the EGFR and IGF-1R signaling networks and the implications of the extensive cross-talk between these two receptor systems for cancer therapy. EGFR and IGF-1R interact on multiple levels, either through a direct association between the two receptors, by mediating the availability of each others ligands, or indirectly, via common interaction partners such as G protein coupled receptors (GPCR) or downstream signaling molecules. This multi-layered cross-talk and its involvement in the induction of resistance to targeted therapies provide a clear rationale for dual targeting of EGFR and IGF-1R. We discuss several (potential) strategies to simultaneously inhibit EGFR and IGF-1R signaling as promising novel therapeutic approaches.