P2-03-02: An IGF1R Antibody Does Not Inhibit Growth of Tamoxifen Resistant MCF-7 Cells.

Abstract

Abstract The role of the insulin-like growth factor (IGF) system in breast cancer has been well defined, and inhibitors of this pathway are currently in clinical trials. The majority of anti-IGF1R clinical trials are in estrogen receptor-positive patients who have progressed on prior endocrine therapy with some early reports showing no benefit for addition of IGF1R inhibitors to endocrine therapy. The effect in endocrine-resistant models, mimicking the clinical trial scenario, has not been adequately investigated. To examine the effectiveness of IGF1R inhibitors in vitro, tamoxifen-resistant (TamR) cells were generated by culturing MCF-7L cells in the presence of 4-hydroxy-tamoxifen for more than 1 year. TamR cells had diminished levels of IGF1R with unchanged levels of insulin receptor (IR), and enhanced phosphorylation of Akt. Further, TamR cells failed to further respond to IGF-I-induced Akt activation while retaining responsiveness to both insulin and IGF-II. Additionally, IGF-I failed to enhance the proliferation and anchorage-independent growth of TamR cells; however, both insulin and IGF-II stimulated proliferation and anchorage-independent growth. An IGF1R antibody (dalotuzumab) was able to inhibit IGF-I-mediated Akt phosphorylation, proliferation, and anchorage-independent growth in parental MCF-7L cells and had minimal effect on insulin and IGF-II stimulation. In TamR cells, dalotuzumab failed to inhibit proliferation or anchorage-independent growth in response to either insulin or IGF-II. An IGF1R tyrosine kinase inhibitor, (AEW 541) with equal potency for the IGF1R and IR, inhibited IGF-I-, IGF-II-, and insulin-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in MCF-7L parental cells. Interestingly, AEW 541 also inhibited insulin- and IGF-II-stimulated Akt phosphorylation, proliferation, and anchorage-independent growth in MCF-7L TamR cells. We conclude that cells selected for tamoxifen resistance in vitro have downregulated IGF1R making antibodies directed against this receptor ineffective. Preliminary studies in vivo, suggest that initial co-treatment with tamoxifen plus dalotuzumab was more effective than either drug alone. In contrast, acquired tamoxifen resistance might require dual inhibition of IGF1R and PI3K targets to completely suppress IGF system signaling as currently under study in the clinic. Alternatively, IGF1R tyrosine kinase inhibitors may be effective by inhibiting both IGF1R and IR signaling in cells selected for tamoxifen resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-03-02.