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Beatty A , Fink LS , Singh T , Strigun A , Peter E , Ferrer CM , Nicolas E , Cai KQ , Moran TP , Reginato MJ , Rennefahrt U , Peterson JR
Metabolite profiling reveals the glutathione biosynthetic pathway as a therapeutic target in triple negative breast cancer
Mol Cancer Ther. 2018 Jan;17(1) :264-275
PMID: 29021292    PMCID: PMC5892195    URL: https://www.ncbi.nlm.nih.gov/pubmed/29021292
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Cancer cells can exhibit altered dependency on specific metabolic pathways and targeting these dependencies is a promising therapeutic strategy. Triple negative breast cancer (TNBC) is an aggressive and genomically heterogeneous subset of breast cancer that is resistant to existing targeted therapies. To identify metabolic pathway dependencies in TNBC, we first conducted mass spectrometry-based metabolomics of TNBC and control cells. Relative levels of intracellular metabolites distinguished TNBC from non-transformed breast epithelia and revealed two metabolic subtypes within TNBC that correlate with markers of basal-like versus non-basal-like status. Among the distinguishing metabolites, levels of the cellular redox buffer glutathione were lower in TNBC cell lines compared to controls and markedly lower in non-basal-like TNBC. Significantly, these cell lines showed enhanced sensitivity to pharmacological inhibition of glutathione biosynthesis that was rescued by N-acetylcysteine, demonstrating a dependence on glutathione production to suppress ROS and support tumor cell survival. Consistent with this, patients whose tumors express elevated levels of gamma-glutamylcysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, had significantly poorer survival. We find, further, that agents that limit the availability of glutathione precursors enhance both glutathione depletion and TNBC cell killing by gamma-glutamylcysteine ligase inhibitors in vitro. Importantly, we demonstrate the ability to this approach to suppress glutathione levels and TNBC xenograft growth in vivo. Overall, these findings support the potential of targeting the glutathione biosynthetic pathway as a therapeutic strategy in TNBC and identify the non-basal-like subset as most likely to respond.
1538-8514 Beatty, Alexander Fink, Lauren S Singh, Tanu Strigun, Alexander Peter, Erik Ferrer, Christina M Nicolas, Emmanuelle Cai, Kathy Q Moran, Timothy P Reginato, Mauricio J Rennefahrt, Ulrike Peterson, Jeffrey R R01 GM083025/GM/NIGMS NIH HHS/United States Journal Article United States Mol Cancer Ther. 2017 Oct 11. pii: molcanther.0407.2017. doi: 10.1158/1535-7163.MCT-17-0407.