ERRα-Regulated Lactate Metabolism Contributes to Resistance to Targeted Therapies in Breast Cancer

• Oxidation of lactate allows breast cancer cells to withstand fluctuations in glucose availability
• ERRα antagonists disrupt mitochondrial function, inhibit lactate utilization, and compromise cancer cell viability
• Breast cancer cells utilizing lactate are insensitive to PI3K/mTOR inhibitors
• ERRα antagonists increase the activity of clinically relevant PI3K/mTOR inhibitors

SummaryImaging studies in animals and in humans have indicated that the oxygenation and nutritional status of solid tumors is dynamic. Furthermore, the extremely low level of glucose within tumors, while reflecting its rapid uptake and metabolism, also suggests that cancer cells must rely on other energy sources in some circumstances. Here, we find that some breast cancer cells can switch to utilizing lactate as a primary source of energy, allowing them to survive glucose deprivation for extended periods, and that this activity confers resistance to PI3K/mTOR inhibitors. The nuclear receptor, estrogen-related receptor alpha (ERRα), was shown to regulate the expression of genes required for lactate utilization, and isotopomer analysis revealed that genetic or pharmacological inhibition of ERRα activity compromised lactate oxidation. Importantly, ERRα antagonists increased the in vitro and in vivo efficacy of PI3K/mTOR inhibitors, highlighting the potential clinical utility of this drug combination.

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