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


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.
Esparís-Ogando
A
A
Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
Ocaña
A
A
Rodríguez-Barrueco
R
R
Ferreira
L
L
Borges
J
J
Pandiella
A
A
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011743:Pyrimidines; D011758:Pyrroles; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab; C501177:NVP-AEW541