Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy

Abstract

Introduction: The IGF system controls growth, differentiation, and development at the cellular, organ and organismal levels. IGF1 receptor (IGF1R) signaling is dysregulated in many cancers. Numerous clinical trials are currently assessing therapies that inhibit either growth factor binding or IGF1R itself. Therapeutic benefit, often in the form of stable disease, has been reported for many different cancer types.

Areas covered: Canonical IGF signaling and non-canonical pathways involved in carcinogenesis. Three recent insights into IGF1R signaling, namely hybrid receptor formation with insulin receptor (INSR), insulin receptor substrate 1 nuclear translocation, and evidence for IGF1R/INSR as dependence receptors. Different approaches to targeting IGF1R and mechanisms of acquired resistance. Possible mechanisms by which IGF1R signaling supports carcinogenesis and specific examples in different human tumors.

Expert opinion: Pre-clinical data justifies IGF1R as a target and early clinical trials have shown modest efficacy in selected tumor types. Future work will focus upon assessing the usefulness or disadvantages of simultaneously targeting the IGF1R and INSR, biomarker development to identify potentially responsive patients, and the use of IGF1R inhibitors in combination therapies or as an adjunct to conventional chemotherapy.

Keywords:

• cancer
• dependence receptor
• insulin receptor (IR)
• insulin-like growth factor receptor (IGF1R)
• IRS proteins
• PI3K-Akt
• Ras-MAPK
• targeted therapy
• tyrosine kinase inhibitor (TKI)

Acknowledgement

The authors would like to thank J Rowlands from Multimedia Services (BCCA) for her assistance in preparing the figures for this review.

Notes

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