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

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.

• Authors: A Esparís-Ogando, A Ocaña, R Rodríguez-Barrueco, L Ferreira, J Borges, A Pandiella
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 19 Issue 11 Pg. 1860-9 (Nov 2008) ISSN: 1569-8041 [Electronic] England
• PMID: 18641009 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• NVP-AEW541
• Pyrimidines
• Pyrroles
• Receptor, ErbB-2
• Receptor, IGF Type 1
• Trastuzumab

Topics

• Antibodies, Monoclonal (administration & dosage, pharmacology)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Breast Neoplasms (drug therapy, enzymology, metabolism)
• Cell Line, Tumor
• Drug Synergism
• Humans
• Pyrimidines (administration & dosage, pharmacology)
• Pyrroles (administration & dosage, pharmacology)
• Receptor, ErbB-2 (biosynthesis)
• Receptor, IGF Type 1 (antagonists & inhibitors, biosynthesis)
• Trastuzumab