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Mechanisms of Disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer

Nature Clinical Practice Oncology volume 4, pages 591–602 (2007)Cite this article

Abstract

The insulin-like growth factor 1 (IGF1) signaling pathway is implicated in the development of cancer. High levels of circulating IGF1 and certain genetic polymorphisms of IGF1 and IGFBP3 are associated with an increased risk of several common cancers. The IGF1 receptor (IGF1R) has been shown to be expressed in a wide range of tumors, and IGF1R signaling is crucial for tumor transformation and the survival of malignant cells. Several monoclonal antibodies and small-molecule inhibitors have been tested in preclinical studies and early-phase clinical studies. IGF1R signaling interferes with numerous growth factors and receptors such as VEGF and EGFR. In the experimental system, IGF1R signaling has been found to correlate with resistance to therapies based on the inhibition of EGFR and HER2. This Review highlights the most relevant studies in this exciting area of research, focusing in particular on the role of IGF1R in resistance to other receptor-targeted therapies for cancer.

Key Points

  • IGF1R is expressed in a large range of tumors and is crucial for tumor transformation and survival of malignant cells

  • IGF1R signaling interferes with numerous growth factors and receptors pathways such as VEGF and EGFR, and IGF1R signaling has been found to correlate with resistance to both anti-EGFR therapies and those that target HER2

  • Several monoclonal antibodies and smallmolecular inhibitors are being tested in preclinical and clinical studies; these compounds would need to distinguish between the highly homologous tyrosine kinase domain of the IGF1R and the insulin receptor

  • Inhibition of IGF1R could be particularly useful in combination with other anticancer therapies because of its strong antiapoptotic activity and interplay with crucial tumor signals such as EGFR, mTOR, VEGF

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Figure 1: Schematic diagram of the insulin-like growth factor 1 receptor pathway.

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Acknowledgements

The authors thank Lorna Saint Ange for her assistance in editing this manuscript.

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Authors and Affiliations

  1. Y Tao is a Radiation Oncology Clinical Fellow at both the Institute Gustave-Roussy and the Department of Radiation Oncology of Cancer Hospital, Fu Dan University, Shanghai, China.,

    Yungan Tao

  2. J Bourhis is Head of the Radiation Oncology Department and E Deutsch is a Radiation Oncologist, V Pinzi is a Radiation Oncologist, all at the Institute Gustave Roussy, Villejuif, France.,

    Valentina Pinzi, Jean Bourhis & Eric Deutsch

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Tao, Y., Pinzi, V., Bourhis, J. et al. Mechanisms of Disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer. Nat Rev Clin Oncol 4, 591–602 (2007). https://doi.org/10.1038/ncponc0934

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