Despite significant improvement in the treatment outcome of hormone responsive post-menopausal breast cancer, some eventually acquire resistance to AIs. Using our MCF-7Ca xenograft model, we observed that although, AI anastrozole inhibited tumor growth, tumors eventually began to grow. Our previous data shows that anastrozole resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. In the current study, we investigated the effect of inhibiting the growth factor receptor pathways with two signal transduction inhibitors. We treated the mice with anastrozole resistant tumors with selumetinib (AZD6244, ARRY-142866); an MEK 1/2 inhibitor and AZD8055; a dual mTORC1 and mTORC2 inhibitor, alone or in combination with anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented with androstenedione (100 μg/d), the substrate for aromatase conversion to estrogen. Once the tumors reached a size of ∼300mm3, the mice were assigned to one of two treatment groups so that mean tumor volumes were not significantly different (p=0.98) at the start of treatment: control, anastrozole (200μg/d). All animals continued to be supplemented with androstenedione (≥4A). The tumors in the anastrozole group doubled after 6 weeks. At week 6, the animals were regrouped into six groups such that the mean tumor volumes were not significantly different (p=0.18). The mice received the following treatments (i) anastrozole, (ii) anastrozole withdrawal (≥4A alone), (iii) selumetinib (25mg/kg/d, bid, po), (iv) selumetinib + anastrozole, (v) AZD8055 (20mg/kg/d, po), (vi) AZD8055 + anastrozole (n=10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, tumors were collected and analyzed. Using mixed effects model, the growth rates of tumors (≥i) between different groups of treatments were compared. The tumors of mice treated with selumetinib + anastrozole had significantly lower growth rate than both single agents (p=0.008). The growth rate of tumors of mice treated with AZD8055 + anastrozole was marginally lower than the single agents (p=0.058). Western blotting analysis of the tumors showed that treatment with anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. This suggests that anastrozole resistance results in adaptation of the tumors to growth factor receptor pathway. When the tumors were treated with signal transduction inhibitors such as selumetinib or AZD8055, the respective pathways were effectively inhibited, which resulted in upregulation of ERα. Our results suggest that inhibition of growth factor receptor pathway with selumetinib or AZD8055 can reverse anastrozole resistance.

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 2919. doi:1538-7445.AM2012-2919