Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells.
BACKGROUND
The humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin) is useful in the treatment of ErbB2-overexpressing breast cancers, but its efficiency is limited because development of resistance is common. In order to study the possibility of improving the efficacy of therapies directed against HER2/erbB2, we investigated the effects of co-targeting this receptor and the insulin-like growth factor 1 receptor (IGF-1R), a widely-expressed protein tyrosine kinase with important roles in suppression of apoptosis and stimulation of proliferation.


METHODS
The experimental strategy involved combining trastuzumab treatment and reduction of IGF-1R signaling through incremental heat-induced expression of the dominant-negative IGF-1 receptor 486/STOP under the control of the heat-sensitive Drosophila HSP70 promoter, in HER2/erbB2-overexpressing MCF7her18 breast cancer cells.


RESULTS
Isobologram analysis of combinatorial treatment data revealed a strong synergistic interaction between trastuzumab treatment and the induction of the dominant-negative IGF-1R expression, resulting in potentiation of growth inhibition in transfected cancer cells.


CONCLUSIONS
These observations support the concept that simultaneously co-targeting tyrosine kinase receptors may be therapeutically useful, and provide a specific rationale for combining IGF-1R and HER2/erbB2 targeting strategies in anti-neoplastic approaches.
Camirand
Anne
A
Department of Oncology, McGill University, Montréal, QC, Canada. ame.camirand@mail.mcgill.ca
Lu
Yuhong
Y
Pollak
Michael
M
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D010957:Plasmids / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013696:Temperature; D014162:Transfection; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab