Abstract P4-07-03: Rapamycin and Dalotuzumab in combination inhibit parental and endocrine resistant breast cancer cells.

Abstract

Abstract The PI3K/Akt/mTOR pathway is involved in breast cancer resistance to endocrine therapy. Inhibitors of mTOR have been shown to have benefit for patients with ER positive tumors that have developed endocrine therapy resistance. Inhibition of mTOR triggers a negative feedback loop resulting in enhanced phosphorylation of Akt and subsequent breast cancer cell proliferation via the IGF signaling pathway. Therefore, blockade of both IGF-1R and mTOR may be necessary to completely suppress this pathway. Our laboratory studied the effect of dual inhibition of mTOR and IGF-1R with rapamycin and dalotuzumab respectively on parental and endocrine resistant MCF-7 breast cancer cell tumorigenesis. Immunoblotting demonstrates parental MCF-7L cells treated with rapamycin alone demonstrate increased phosphorylation of Akt. Inhibition of phosphorylation of Akt can be achieved with combined treatment with rapamycin and dalotuzumab at concentrations of 5 nM and 2 µg/mL respectively. In addition to inhibition of pAkt, combined treatment inhibits phosphorylation of S6K1 and the translational repressor protein, 4eBP1. Furthermore, MTT proliferation assay and soft agar assay demonstrate inhibition of parental cell proliferation and colonization respectively with combined rapamycin and dalotuzumab treatment. In order to examine the effect of combination therapy in endocrine resistant cell lines, we established tamoxifen resistant (TamR) and long term estrogen deprived (LTED) cell lines. TamR cells were generated by culturing MCF-7L cells in the presence of tamoxifen for more than 1 year. LTED cells were generated by culturing MCF-7L cells in the absence of estrogen for more than 6 months. Proliferation of TamR and LTED cells treated with rapamycin at a concentration of 5nM and dalotuzumab at a concentration of 2µg/mL in combination was significantly inhibited. We conclude that combination of IGF1R and mTOR inhibition might be necessary to inhibit endocrine resistant breast cancers. Ongoing clinical trials will test this combination of drugs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-07-03.