Abstract
Abstract Background: Aerobic glycolysis, commonly used by cancer cells, converts glucose to lactate regardless of available oxygen. 2-Deoxyglucose (2DG), a glucose metabolism inhibitor, inhibits hexokinase enzyme activity, and can be used in functional tumor imaging, which can enhance efficacy of chemotherapy and radiotherapy in solid tumors. Lapatinib, a HER kinase inhibitor, is used for HER2+ breast cancer treatment, but is limited in efficacy due to emergence of therapeutic resistance. However, data investigating combination of 2DG + lapatinib in HER2+ BC are limited. In this study, we evaluated whether 2DG enhances lapatinib sensitivity in lapatinib-sensitive and resistant HER2+ cells. Materials and methods: SKBR3 and BT474 cells were treated with increasing dose of lapatinib to develop lapatinib-resistant cells: SKBR3-LapR and BT474-LapR. Potential synergism between 2DG and lapatinib was evaluated by viability assays, and calculated via CalcuSyn software or relative risk ratios (RRRs). Glycolysis was monitored in response to drug treatments via western blots and assays for lactate production, glucose uptake, and hexokinase activity. Results: Lapatinib treatment significantly inhibited glycolysis in SKBR3 and BT474 cell lines (P < 0.01). Combination lapatinib + 2DG was synergistic in inhibiting SKBR3 and BT474 proliferation, with average IC50 values of 0.53±0.16 and 0.55±0.01, respectively. SKBR3-LapR cells exhibited higher rates of lactate production, glucose uptake and hexokinase activity compared to lapatinib-sensitive cells (P < 0.05), and BT474-LapR cells exhibited higher hexokinase activity (P < 0.001) and glucose uptake (P < 0.05). RRRs were less than 1 with 2DG + lapatinib combination in SKBR3-LapR (0.88-0.98) and BT474-LapR (0.76-0.96) cells. Moreover, 2DG + lapatinib induced greater apoptosis, especially in lapatinib-resistant cells (P = 0.004 and 0.003 for SKBR3-LapR and BT474-LapR cells, respectively). Finally, 2DG + lapatinib inhibited several steps of the glycolytic pathway, namely: reduction of hexokinase II expression levels, inhibition of lactate production, decreased glucose uptake and impaired hexokinase activity, in both lapatinib-sensitive and resistant cells. Conclusion: 2DG can enhance lapatinib sensitivity by inhibiting aerobic glycolysis in both naïve and lapatinib-resistant HER2+ breast cancer cells. 2DG impinges on multiple steps of glycolysis, and combination with lapatinib may serve to prevent and/ or ameliorate therapeutic resistance in patients treated with lapatinib. Citation Format: Xiaosong Chen, Junjun Liu, Toby Ward, Xiaofei Liu, Yan Mao, Jessica Bockhorn, Kunwei Shen, Mark Pegram. Targeting glycolytic pathway with 2-Deoxy-glucose enhances lapatinib sensitivity in HER2-amplified breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 713. doi:10.1158/1538-7445.AM2015-713
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