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Efficacy of and resistance to anti‐IGF‐1R therapies in sarcomas is dependent on Insulin Receptor signaling

Garofalo, Cecilia and Manara, Maria Christina and Nicoletti, Giordano and Marino, Maria Theresa and Nanni, Patrizia and Lollini, Pier-Luigi and Prandini, Giuseppe and Lopez-Guerrero, José Antonio and Schaefer, Karl-Ludwig and Belfiore, Antonino and Picci, Piero and Scotlandi, Katia (2011) Efficacy of and resistance to anti‐IGF‐1R therapies in sarcomas is dependent on Insulin Receptor signaling. Oncogene, 30 (24). pp. 2730-2740. ISSN 0950-9232

Abstract

Identification of patient selection criteria and understanding of the potential mechanisms involved in development of resistance are crucial for an appropriate and successful design of clinical trials with anti-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 IR-A homodimer formation and IGFII production. Resistant cells are able to switch from IGF-I/IGF-1R to IGF-II/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-IGF1R 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 ratios in cancer cells. Moreover, we provide evidences supporting IR-A as an important target in sarcoma therapy.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: sarcomas, IGF-1R, Insulin signaling, drug resistance
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/3221

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