Annals of Oncology Advance Access published online on July 17, 2008
Annals of Oncology, doi:10.1093/annonc/mdn406
Synergic antitumoral effect of an IGF-IR inhibitor and trastuzumab on HER2-overexpressing breast cancer cells
1 Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca
2 Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, Spain
* Correspondence to: Dr A. Pandiella, Instituto de Biología Molecular y Celular del Cáncer, Campus Miguel de Unamuno, 37007-Salamanca, Spain. Tel/Fax: +34-923-294815; E-mail: atanasio{at}usal.es
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.
breast cancer, IGF-IR, trastuzumab
These authors contributed equally to the work. Received for publication March 4, 2008. Revision received May 30, 2008. Accepted for publication June 2, 2008.