Endocrine therapies directed against estrogen action are initially effective in estrogen-receptor positive (ER+) breast cancer, though most patients will eventually develop resistance to these treatments. It has recently been shown that growth factor signaling can activate ER through the AKT and MAPK signaling pathways. Moreover, both heregulin and ErbB3 signaling have been implicated as potential escape routes in the development of resistance to anti-estrogen therapies. Here we have used an in vivo model of ER+ breast cancer to investigate the activity of MM-121/SAR256212, alone and in combination with the aromatase inhibitor letrozole.
Tumor xenografts of human breast cancer cells (MCF-7) engineered to express aromatase (MCF7-Ca) were generated in ovariectomized athymic nude mice. Mice were injected daily with androstenedione and randomized to treatment groups once the average tumor volume per group reached ∼300 mm3. Mice received vehicle, letrozole, MM-121, or both MM-121 and letrozole. Following development of resistance to letrozole, mice receiving letrozole alone were re-distributed into three treatment groups - letrozole, MM-121, or letrozole plus MM-121. Tumors were harvested at 24 h post-treatment initiation, at development of letrozole resistance, and at the end of study. Total and phosphorylated levels of certain signaling proteins in the ErbB network were measured by quantitative Western blotting.
MM-121 in combination with letrozole significantly inhibited tumor growth (p<0.05) in our in vivo model. Further, when MM-121 was dosed with letrozole from the start of the study, a statistically significant delay was observed in the onset of resistance to letrozole (p=0.01; Letrozole vs. Let+MM-121/SAR256212). Following development of letrozole resistance, the addition of MM-121 restored sensitivity to letrozole and slowed the rate of tumor growth (p<0.0001; Letrozole vs. Let to Let+MM-121/SAR256212). Molecular analyses indicated decreased tErbB3 and pErbB3 levels in MM-121/SAR256212 treated tumors. As previously shown, tHER2 levels were elevated following development of letrozole resistance. Moreover, pS6 levels were decreased following continuous MM-121/SAR256212 and letrozole treatment, indicating decreased mRNA translation.
In conclusion, MM-121 delayed the onset of resistance to letrozole in this in vivo model, and re-sensitized tumors to letrozole upon development of resistance. These data indicate a potential role for combining MM-121 with letrozole in first and second line treatment of ER+ breast cancer.
Citation Format: Michael D. Curley, Gauri Sabnis, Lucia Wille, Gabriela Garcia, Victor Moyo, Armina Kazi, Gavin MacBeath, Angela Brodie. MM-121/SAR256212, an anti-ErbB3 antibody, restores sensitivity to letrozole and delays the onset of resistance in an ER+ breast cancer model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2013-1072