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

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.