Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets
Yue Gong, Peng Ji, Yun-Song Yang, Shao Xie, Tian-Jian Yu, Yi Xiao, Ming-Liang Jin, Ding Ma, Lin-Wei Guo, Yu-Chen Pei, Wen-Jun Chai, Da-Qiang Li, Fan Bai, François Bertucci, Xin Hu, Yi-Zhou Jiang, Zhi-Ming Shao, Yue Gong, Peng Ji, Yun-Song Yang, Shao Xie, Tian-Jian Yu, Yi Xiao, Ming-Liang Jin, Ding Ma, Lin-Wei Guo, Yu-Chen Pei, Wen-Jun Chai, Da-Qiang Li, Fan Bai, François Bertucci, Xin Hu, Yi-Zhou Jiang, Zhi-Ming Shao
Abstract
Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.
Keywords: glycolysis; heterogeneity; immunotherapy; metabolic inhibitor; metabolic pathway; metabolism; subtype; survival; triple-negative breast cancer.
Conflict of interest statement
Declaration of Interests The authors declare no competing interests.
Copyright © 2020 Elsevier Inc. All rights reserved.
Source: PubMed