Browse views: by Year, by Function, by GLF, by Subfunction, by Conference, by Journal

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

Garofalo, Cecilia, Manara, Maria Christina, Nicoletti, Giordano, Marino, Maria Theresa, Nanni, Patrizia, Lollini, Pier-Luigi, Prandini, Giuseppe, Lopez-Guerrero, José Antonio, Schaefer, Karl-Ludwig, Belfiore, Antonino, 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


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
Related URLs:
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
Related URLs:
Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16