Abstract 2861: Inhibition of mTOR and AKT as a potential strategy for the treatment of basal-like breast cancer

Abstract

Abstract Basal-like breast cancer is an aggressive disease, for which effective targeted therapies are lacking. The frequent loss of phosphatase and tensin homolog (PTEN) and aberrant activation of phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR pathway in basal-like breast cancer make it an attractive therapeutic strategy to target AKT and mTOR. To evaluate the effect of PTEN loss on tumor cell sensitivity to mTOR inhibition, we performed PTEN knockdown experiment in vitro using a basal-like breast cancer cell line WU-BC3, which was derived from a patient with triple negative breast cancer. A more dramatic reduction in cell proliferation was observed in WU-BC3 siPTEN compared to that in WU-BC3 siControl following 7 days of treatment with the mTOR inhibitor MK-8669 (p<0.001). We then tested MK-8669 and MK-2206 (an allosteric, selective pan-AKT inhibitor), either alone or in combination, in 2 Human Tumor in Mouse (HIM) models of basal-like breast cancer, WU-BC4 and WU-BC5, that are deficient in PTEN expression in vivo. In both models, MK-8669 alone significantly inhibited tumor growth (p<0.001). However, the combination of MK-8669 and MK-2206 was more effective than either MK-8669 (p<0.05) or MK-2206 (p<0.01) alone. Biomarker studies indicated that the combination therapy resulted in a more dramatic inhibition of tumor cell proliferation (as assessed by Ki67) and angiogenesis (as assessed by CD31 staining) than single agents alone in both models. In addition, treatment with MK-2206 abolished the MK-8669-induced AKT activation in vivo, suggesting the inhibition of the feedback loop between mTOR and AKT being a potential underlying mechanism for the enhanced anti-tumor effect observed with the combination therapy. Our results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer. 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 2861. doi:1538-7445.AM2012-2861