Efficacy of and resistance to anti-IGF-1R therapies in Ewing's sarcoma is dependent on insulin receptor signaling
| Autor: | Cecilia Garofalo, Katia Scotlandi, Pier Luigi Lollini, Giuseppe Pandini, M.C. Manara, Giordano Nicoletti, Antonino Belfiore, Jose Antonio López-Guerrero, Annalisa Astolfi, Karl-Ludwig Schaefer, P. Picci, Maria Teresa Marino |
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| Přispěvatelé: | C. Garofalo, M. C. Manara, G. Nicoletti, M.T. Marino, P.-L. Lollini, A. Astolfi, G. Pandini, J.A. López-Guerrero, K.L. Schaefer, A. Belfiore, P. Picci, K. Scotlandi. |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
medicine.medical_treatment Sarcoma Ewing Antibodies Metastasis Receptor IGF Type 1 Cell Line Mice IGF1R Cell Line Tumor Ewing Monoclonal medicine Genetics Animals Humans Insulin IGF Type 1 sarcomas Protein kinase B insulin signaling Molecular Biology drug resistance Tumor biology IGF-1R Antibodies Monoclonal Drug Resistance Neoplasm Female Receptor Insulin Signal Transduction Cancer Sarcoma medicine.disease Insulin receptor Immunology Cancer cell biology.protein Cancer research Neoplasm Tyrosine kinase Receptor |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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