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

被引:0
作者
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
机构
[1] Laboratory of Experimental Oncology,Department of Hematology and Oncology Sciences L. A. Seràgnoli
[2] Istituto Ortopedico Rizzoli,Department of Internal Medicine and Medical Specialties
[3] Sant'Orsola-Malpighi Hospital,Department of Clinical and Experimental Medicine
[4] University of Bologna,undefined
[5] G.Prodi Cancer Research Center,undefined
[6] University of Bologna,undefined
[7] Endocrinology,undefined
[8] University of Catania,undefined
[9] Catania,undefined
[10] Laboratory of Molecular Biology,undefined
[11] Fundación Instituto Valenciano de Oncología,undefined
[12] University Medical Center,undefined
[13] Inst. f. Pathology,undefined
[14] University of Catanzaro,undefined
[15] Catanzaro,undefined
[16] CRS Development of Biomolecular Therapies,undefined
[17] Istituto Ortopedico Rizzoli,undefined
来源
Oncogene | 2011年 / 30卷
关键词
sarcomas; IGF-1R; insulin signaling; drug resistance;
D O I
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学科分类号
摘要
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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页码:2730 / 2740
页数:10
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