Abstract 2702: Effects of Src and IGF1R inhibition on acquired endocrine therapy resistant breast cancer

Abstract

Abstract Effective standard therapy for hormone receptor-positive (HR+) breast cancer targets the estrogen receptor (ER). However, a significant proportion of women with HR+ breast cancer relapse. Furthermore, the majority of women with metastatic HR+ breast cancer develop resistance to endocrine therapy. Adaptive cross-talk between ER and growth factor receptor pathways including IGF1R and Src is involved in acquired endocrine therapy resistance. To determine effects of adding dasatinib (D), Src inhibitor, and/or anti-IGF1R Ab MK0646 (M) to the ER antagonist fulvestrant (F) in an acquired endocrine therapy resistant breast cancer, we used long-term estrogen-deprived (LTED) derivative of ER+ breast cancer cell lines, MCF-7/LTED and HCC-1428/LTED. Parental and LTED cells were treated with variable combinations of F, D and M, followed by determinations of drug effects on cell growth, migration, and invasion in vitro and tumor growth in vivo. We demonstrated that LTED cells were resistant to F alone, comparing parental cells (P<0.05) in cell growth, migration and invasion. Addition of D to F appeared to be synergistic in all systems including cell growth, cell migration and invasion. However, the addition of M to F or to F+D appeared inhibition on cell growth in monolayer with low-serum medium, but not to significantly add inhibitory effects on cell growth in 3D and cell migration and invasion. The effects of IGF-1R antibody, MK0646, on cells growth in monolayer showed not consistent with 3D, which might be due to growth factors in the matrigel, although we used growth factors decreased matrigel. To verify the effects of the drugs on tumor growth in vivo, we developed xenograft models using MCF-7/LTED cells and treated the mice with F, D, and M along or variable combinations. The study demonstrated that all the combinations of F+D+M, F+D, and F+M (from P< 0.05 to <0.001 in viable time points) show inhibited the tumor growth comparing vehicle or F alone. The inhibitory effect of F+D+M is higher than F+D and F+M. In summary, the addition of dasatinib to fulvestrant appeared to be synergistic in all systems including cell growth, cell migration and invasion and tumor growth in vivo. The addition of MK0646 to fulvestrant mildly inhibited MCF-7/LTED cell growth and xenografts growth, but not cell migration and cell invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2702. doi:1538-7445.AM2012-2702