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Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells

AuthorsEsparís-Ogando, Azucena ; Ocaña, Alberto; Rodríguez-Barrueco, Ruth; Ferreira, Laura; Borges, Joana; Pandiella, Atanasio
Issue Date2008
PublisherOxford University Press
CitationAnnals of Oncology 19(11): 1860-1869 (2008)
Abstract[Background]: Receptor tyrosine kinases play an important role in breast cancer. One of them, the type I insulin-like growth factor, has been linked to resistance to trastuzumab (Herceptin), an agent that targets human epidermal growth factor receptor 2. Here, we show that the insulin-like growth factor-I receptor (IGF-IR) antagonist NVP-AEW541 inhibits proliferation of breast cancer cells and synergizes with trastuzumab. [Patients and methods]: Patient samples and breast cancer cell lines were evaluated for IGF-IR expression or activation by western blotting. 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) uptake assays and Annexin V staining were used for the analyses of cell proliferation/ apoptosis. Biochemical and genomic studies were carried out to gain insights into the mechanism of action of NVP-AEW541. [Results]: The IGF-IR was expressed above normal levels in a number of breast cancer samples. Activation of this receptor was inhibited by NVP-AEW541 that also decreased cell proliferation and increased apoptosis. NVP-AEW541 decreased the amount of pAkt and increased the level of p27. Combination studies with several drugs used in the breast cancer clinic showed that NVP-AEW541 synergistically increased the action of trastuzumab. Conclusions: Our results show the anti-breast cancer action of NVP-AEW541 and support the clinical development of anti-IGF-IR agents, especially in combination with trastuzumab. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.
Identifiersdoi: 10.1093/annonc/mdn406
issn: 0923-7534
e-issn: 1569-8041
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