De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Shi, Diana D.; Savani, Milan R.; Levitt, Michael M.; Wang, Adam C.; Endress, Jennifer E.; Bird, Cylaina E; Buehler, Joseph D; Stopka, Sylwia A.; Regan, Michael S.; Lin, Yu‐Fen; Puliyappadamba, Vinesh T.; Gao, Wenhua; Khanal, Januka; Evans, Laura; Lee, Joyce H.; Guo, Lei; Xiao, Yi; Xu, Min; Huang, Bofu; Jennings, Rebecca B.; Bonal, Dennis M.; Martin-Sandoval, Misty S.; Dang, Tammie; Gattie, Lauren C; Cameron, Amy B.; Lee, Sung‐Woo; Asara, John M.; Kornblum, Harley I.; Mak, Tak W.; Looper, Ryan; Nguyen, Quang-Dé; Signoretti, Sabina; Gradl, Stefan; Sutter, Andreas; Jeffers, Michael; Janzer, Andreas; Lehrman, Mark A.; Zacharias, Lauren G.; Mathews, Thomas P.; Losman, Julie-Aurore; Richardson, Timothy E.; Cahill, Daniel P.; DeBerardinis, Ralph J.; Ligon, Keith L.; Xu, Lin; Ly, Peter; Agar, Nathalie Y.R.; Abdullah, Kalil G.; Harris, Isaac S.; Kaelin, William G.; McBrayer, Samuel K.

doi:10.1016/j.ccell.2022.07.011

Cited by 50 publications

(33 citation statements)

References 66 publications

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“…Therefore, reduced levels of dTMP may indicate reduced proliferation attributable to radiation, which may be reflected in the increased survival of the cohort undergoing RT. These results are interesting since de novo pyrimidine synthesis has been recently reported as a novel vulnerability in the IDH1-mutant astrocytoma models and suggests the potential for combining RT with de novo pyrimidine synthesis inhibitors ( 35 ).…”

Section: Discussionmentioning

confidence: 74%

“…Tumors harboring a mutation in the IDH1 gene have been reported to present an enhanced sensitivity to radiation due to the modification of the epigenetic landscape by 2HG that affects the DNA damage responses ( 34 ). In addition, de novo pyrimidine pathway which contributes precursors to DNA synthesis has been recently reported to be a vulnerability of IDH1-mutated astrocytoma ( 35 ). The RT vulnerability has been exploited in IDH1-mutant tumors revealing a beneficial effect in response to radiation ( 36 ), as observed in our model as well ( Figure 1B ).…”

Section: Discussionmentioning

confidence: 99%

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Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Ruiz‐Rodado

Dowdy²,

Lita³

et al. 2022

Front. Oncol.

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Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Ruiz‐Rodado

Dowdy²,

Lita³

et al. 2022

Front. Oncol.

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“…Additionally, exclusive mutations of IDH1 were plotted ( Supplementary Figure 4C ). Two recent studies ( 40 , 41 ) revealed that IDH1-mutant glioma cells are hypersensitive to drugs targeting enzymes in the de novo pyrimidine nucleotide synthesis pathway. As a major material in the process of synthesizing pyrimidine, glutamine is catalyzed by carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, dihydroorotase (CAD) to supply nitrogen to the pyrimidine, which has become a key step in the synthesis of pyrimidine.…”

Section: Resultsmentioning

confidence: 99%

Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment

Shi²,

Yao³

et al. 2022

Front. Oncol.

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IntroductionGlutamine is characterized as the nutrient required in tumor cells. The study based on glutamine metabolism aimed to develop a new predictive factor for pan-cancer prognostic and therapeutic analyses and to explore the mechanisms underlying the development of cancer.MethodsThe RNA-sequence data retrieved from TCGA, ICGC, GEO, and CGGA databases were applied to train and further validate our signature. Single-cell RNA transcriptome data from GEO were used to investigate the correlation between glutamine metabolism and cell cycle progression. A series of bioinformatics and machine learning approaches were applied to accomplish the statistical analyses in this study.ResultsAs an individual risk factor, our signature could predict the overall survival (OS) and immunotherapy responses of patients in the pan-cancer analysis. The nomogram model combined several clinicopathological features, provided the GMscore, a readable measurement to clinically predict the probability of OS and improve the predictive capacity of GMscore. While analyzing the correlations between glutamine metabolism and malignant features of the tumor, we observed that the accumulation of TP53 inactivation might underlie glutamine metabolism with cell cycle progression in cancer. Supposedly, CAD and its upstream genes in glutamine metabolism would be potential targets in the therapy of patients with IDH-mutated glioma. Immune infiltration and sensitivity to anti-cancer drugs have been confirmed in the high-risk group.DiscussionIn summary, glutamine metabolism is significant to the clinical outcomes of patients with pan-cancer and is tightly associated with several hallmarks of a malignant tumor.

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“…Why would cells evolve to preferentially rely on GTP signaling to stimulate DNA repair? Does the primacy for GTP in controlling DNA repair hold true even for cancers that are especially reliant on de novo pyrimidine synthesis for growth (46)(47)(48). Understanding this issue will determine how best to sequence and combine inhibitors of purine and pyrimidine synthesis with standard of care genotoxic agents for these cancers.…”

Section: Discussionmentioning

confidence: 99%

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

Zhou

Zhao

Lin

et al. 2023

Preprint

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How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.

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De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma

Cited by 50 publications

References 66 publications

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model

Turbulence of glutamine metabolism in pan-cancer prognosis and immune microenvironment

GTP signaling links metabolism, DNA repair, and responses to genotoxic stress

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