Abstract

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. MATERIAL/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.

Keywords: Receptor, erbB-2 - antagonists & inhibitors, Receptor, erbB-2 - genetics