Dual Inhibition of PI3K and mTOR Mitigates Compensatory AKT Activation and Improves Tamoxifen Response in Breast Cancer

作者：Chen, Xiaosong; Zhao, Meizhong; Hao, Mingang; Sun, Xueqing; Wang, Jinglong; Mao, Yan; Zu, Lidong; Liu, Junjun; Shen, Yandong; Wang, Jianhua; Shen, Kunwei^*

来源：Molecular Cancer Research, 2013, 11(10): 1269-1278.

DOI：10.1158/1541-7786.MCR-13-0212

• ENDOTHELIAL GROWTH-FACTOR
• ADJUVANT TAMOXIFEN
• MAMMALIAN TARGET
• EVEROLIMUS
• NVP-BEZ235
• RESISTANT
• RAPAMYCIN
• PATHWAY

Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER+ breast cancer cells.
Implications: Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer.

• 出版日期2013-10
• 单位上海交通大学; 上海市闵行区中心医院