Wild-type IDH2 is a therapeutic target for triple-negative breast cancer

Jiang-jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang and Peng Huang ()
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Jiang-jiang Li: Sun Yat-sen University Cancer Center
Tiantian Yu: Sun Yat-sen University Zhongshan School of Medicine
Peiting Zeng: Sun Yat-sen University Cancer Center
Jingyu Tian: Sun Yat-sen University Cancer Center
Panpan Liu: Sun Yat-sen University Cancer Center
Shuang Qiao: Sun Yat-sen University Cancer Center
Shijun Wen: Sun Yat-sen University Cancer Center
Yumin Hu: Sun Yat-sen University Cancer Center
Qiao Liu: Sun Yat-sen University Cancer Center
Wenhua Lu: Sun Yat-sen University Cancer Center
Hui Zhang: Sun Yat-sen University Cancer Center
Peng Huang: Sun Yat-sen University Cancer Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

Date: 2024
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DOI: 10.1038/s41467-024-47536-6

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