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Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling

Abstract

Identification of patient selection criteria and understanding of the potential mechanisms involved in the development of resistance are crucial for an appropriate and successful design of clinical trials with anti-insulin-like growth factor (IGF)-1R therapies. Few Ewing's sarcomas are highly sensitive to IGF-1R targeting and understanding the reason why, may hold the secret to improve successful treatments. In this paper, we show that a major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production. Resistant cells are able to switch from IGF-1/IGF-1R to IGF-2/IR-A dependency to maintain sustained activation of AKT and ERK1/2, proliferation, migration and metastasis. These cells also showed higher proliferative response to insulin, in keeping with a switch towards insulin pathways sustaining proliferation and malignancy, rather than metabolism. Our findings demonstrate a role for IR-A in eliciting intrinsic and adaptive resistance to anti-IGF-1R therapies. Thus, we indicate that tumors with low IGF-1R:IR ratio are unlikely to greatly benefit from anti-IGF-1R therapies and that the efficacy of anti-IGF-1R therapies should be evaluated in relationship to the IR-A:IGF-1R ratio in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.

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Acknowledgements

We thank Cristina Ghinelli and Alba Balladelli for their help in editing the manuscript. Studies are supported by grants from the Italian Association for Cancer Research (KS and AB), the Italian Ministry of Health (Strategico Oncologia RFPS-2006-3-340280; RF2008 to KS); the Italian Ministry of Research and Instruction (PRIN 2009) and the EU project Eurobonet (#018814).

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Garofalo, C., Manara, M., Nicoletti, G. et al. Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling. Oncogene 30, 2730–2740 (2011). https://doi.org/10.1038/onc.2010.640

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Keywords

  • sarcomas
  • IGF-1R
  • insulin signaling
  • drug resistance

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