Seung-Oe Lim 1 , Chia-Wei Li 1 , Weiya Xia 1 , Heng-Huan Lee 1 , Shih-Shin Chang 1 , 5 , Jia Shen 1 , Jennifer L. Hsu 1 , Dan Raftery 6 , 7 , Danijel Djukovic 6 , Haiwei Gu 6 , Wei-Chao Chang 8 , 9 , Hung-Ling Wang 8 , Mong-Liang Chen 8 , Longfei Huo 1 , Chung-Hsuan Chen 9 , Yun Wu 3 , Aysegul Sahin 3 , Samir M. Hanash 2 , 7 , Gabriel N. Hortobagyi 4 , Mien-Chie Hung 1 , 5 , 8 , 10
12 January 2016
Oncogenic signaling reprograms cancer cell metabolism to augment the production of glycolytic metabolites in favor of tumor growth. The ability of cancer cells to evade immunosurveillance and the role of metabolic regulators in T cell functions suggest that oncogene-induced metabolic reprogramming may be linked to immune escape. Epidermal growth factor (EGF) signaling, frequently dysregulated in triple-negative breast cancer (TNBC), is also associated with increased glycolysis. Here, we demonstrated in TNBC cells that EGF signaling activates the first step in glycolysis, but impedes the last step, leading to an accumulation of metabolic intermediates in this pathway. Furthermore, we showed that one of these intermediates, fructose 1,6 bisphosphate (F1,6BP), directly binds to and enhances the activity of the EGF receptor (EGFR), thereby increasing lactate excretion which leads to inhibition of local cytotoxic T cell activity. Notably, combining the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) with the EGFR inhibitor gefitinib effectively suppressed TNBC cell proliferation and tumor growth. Our results illustrate how jointly targeting the EGFR/F1,6BP signaling axis may offer an immediately applicable therapeutic strategy to treat TNBC.