Abstract B125: Antiproliferative and anti-invasive effect of the novel anti-IGF-1R monoclonal antibody R1507 in endocrine-responsive and -resistant breast cancer cell lines

Abstract

Abstract R1507 is a novel insulin-like growth factor type 1 receptor (IGF-1R)-specific, human monoclonal antibody that binds the extracellular domain of the receptor to inhibit ligand binding and promote receptor internalization. IGF-1R signalling has been implicated in both endocrine-responsive and -resistant breast cancer and the IGF-1R identified as a potential therapeutic target to treat these disease states. In the present study we have examined the effect of R1507 in tamoxifen-resistant (Tam-R) and wild-type MCF-7 cells to determine the therapeutic potential of this agent in breast cancer. Both cell lines were exposed to R1507 (3–300 nM) for periods ranging from 1 to 7 days and effects on signalling, growth and invasive capacity were assessed. R1507 treatment of both MCF-7 and Tam-R cells for 24 hours reduced both expression and activity of IGF-1R and this effect was maintained through to 7 days treatment with this antibody. This effect of R1507 was observed both in the absence and presence of ligand (IGF-I and II) stimulation in the two cell lines. In MCF-7 cells the reduction in basal and ligand-stimulated IGF-1R activity was associated with reduced IRS-1 phosphorylation and inhibition of AKT and ERK1/2 activity at day 1 with the reduction in AKT phosphorylation being maintained through to day 7. However, basal and ligand-stimulated ERK1/2 phosphorylation demonstrated some evidence of recovery in the presence of R1507 although a small inhibitory effect was still apparent at day 7. This potent blockade of IGF-1R signalling by R1507 was associated with a significant inhibition of basal and ligand-stimulated cell growth. A similar effect of R1507 on signalling activity was also observed in Tam-R cells with reductions in basal and ligand-stimulated IRS-1 phosphorylation and AKT activity apparent at day 1 through to day 7. However, although prolonged exposure to R1507 also reduced basal and ligand-stimulated levels of phosphorylated EGFR and erbB2 in this cell line, there was no effect of this antibody on ERK1/2 activity at this time point. Indeed, there was evidence of an increase in basal and ligand-stimulated ERK1/2 activity at the higher concentrations of antibody used in this study. Although R1507 abolished ligand-stimulated Tam-R cell growth there was little effect of this antibody on basal growth of these cells. Interestingly, however, R1507 potently reduced the basal and ligand-stimulated invasive capacity of this cell line. In conclusion these studies would suggest that R1507 can potently inhibit IGF-1R signalling in both an endocrine-responsive and -resistant breast cancer cell line. In endocrine-responsive MCF-7 cells this action of R1507 is anti-proliferative, whereas, in Tam-R cells R1507 appears to have potent anti-invasive properties and only modest growth inhibitory activity. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B125.