Journal
ANNALS OF ONCOLOGY
Volume 19, Issue 11, Pages 1860-1869Publisher
ELSEVIER
DOI: 10.1093/annonc/mdn406
Keywords
breast cancer; IGF-IR; trastuzumab
Categories
Funding
- Ministry of Science and Technology of Spain [BFU2006-01813/BMC]
- Scientific Foundation of the Spanish Association for Cancer Research (AECC)
- Instituto de Salud Carlos III [PI061552, CP04/00045]
- Spanish Cancer Centers Network Program [RD06/0020/0041]
- European Community
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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.
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