Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Wu, Hui; Gong, Yue; Ji, Peng; Xie, Yifan; Jiang, Yi‐Zhou; Liu, Guang-yu

doi:10.1186/s13045-022-01263-x

Cited by 72 publications

(110 citation statements)

References 252 publications

(278 reference statements)

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“…Aberrant β-catenin activation promotes immune escape and resistance to immunotherapy in HCC ( 38 – 40 ). Increasing evidence indicates that targeting nucleotide metabolism, including pyrimidine synthesis, can enhance the antitumor response of immunotherapy ( 41 – 44 ). Therefore, targeting AKT2/pyrimidine synthesis is warranted to overcome β-catenin activation–associated resistance of immunotherapy for HCC.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Liu

Gai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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CTNNB1 , encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection–mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

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Section: Discussionmentioning

confidence: 99%

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Liu

Gai

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…The imbalance of purine nucleotide metabolism often occurs in the process of tumor occurrence and development ( Wang X. et al, 2022 ). Many enzymes involved in purine nucleotide anabolism and catabolism are related to the proliferation and drug resistance of tumor cells ( Wu et al, 2022 ). The imbalance of antioxidant and pro-inflammatory properties of uric acid can also induce tumors and promote their progress ( Wang J. et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

et al. 2022

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Background: Hepatocellular carcinoma (HCC) is regarded as one of the most common cancers in the world with a poor prognosis. Patients with HCC often have abnormal purine and uric acid metabolism, but their relationship with prognosis is unclear.Methods: Here, we collected the data of peripheral blood uric acid and clinical data in 50 patients with HCC and analyzed the relationship with prognosis. At the same time, the transcriptome sequencing data of TCGA and GEO databases were collected to analyze the changes in purine metabolic pathway activity and construct a prognosis prediction model. Based on the prognosis prediction model related to purine metabolism, we further looked for the differences in the immune microenvironment and molecular level and provided possible drug targets.Results: We found that the level of serum uric acid was positively correlated with the prognosis of HCC. At the same time, purine metabolism and purine biosynthesis pathway activities were significantly activated in patients with a poor prognosis of HCC. The prognosis prediction model of HCC based on purine metabolism and purine biosynthesis pathway can accurately evaluate the prognosis of patients with HCC. Meanwhile, we found that there were significant changes in tumor immune infiltration microenvironment and biological function at the molecular level in patients with over-activation of purine metabolism and purine biosynthesis pathway. In addition, we found that uric acid level was positively correlated with peripheral blood leukocytes in HCC patients.Conclusion: In this study, we found that the level of peripheral blood uric acid in patients with HCC is correlated with their prognosis. The prognosis of patients with HCC can be accurately predicted through the metabolic process of uric acid and purine.

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“…In addition, lactate can polarize macrophages to a tolerogenic M2-like phenotype ( DePeaux and Delgoffe, 2021 ). Targeting metabolic pathways has been reported to enhance the efficacy of tumour immunotherapy ( Wu H. L. et al, 2022b ; Khodaei et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

N1-methyladenosine methylation-related metabolic genes signature and subtypes for predicting prognosis and immune microenvironment in osteosarcoma

Wang

Cheng

et al. 2022

Front. Genet.

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N1-methyladenosine methylation (m1A), as an important RNA methylation modification, regulates the development of many tumours. Metabolic reprogramming is one of the important features of tumour cells, and it plays a crucial role in tumour development and metastasis. The role of RNA methylation and metabolic reprogramming in osteosarcoma has been widely reported. However, the potential roles and mechanisms of m1A-related metabolic genes (MRmetabolism) in osteosarcoma have not been currently described. All of MRmetabolism were screened, then selected two MRmetabolism by least absolute shrinkage and selection operator and multifactorial regression analysis to construct a prognostic signature. Patients were divided into high-risk and low-risk groups based on the median riskscore of all patients. After randomizing patients into train and test cohorts, the reliability of the prognostic signature was validated in the whole, train and test cohort, respectively. Subsequently, based on the expression profiles of the two MRmetabolism, we performed consensus clustering to classify patients into two clusters. In addition, we explored the immune infiltration status of different risk groups and different clusters by CIBERSORT and single sample gene set enrichment analysis. Also, to better guide individualized treatment, we analyzed the immune checkpoint expression differences and drug sensitivity in the different risk groups and clusters. In conclusion, we constructed a MRmetabolism prognostic signature, which may help to assess patient prognosis, immunotherapy response.

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Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Cited by 72 publications

References 252 publications

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

A Novel Purine and Uric Metabolism Signature Predicting the Prognosis of Hepatocellular Carcinoma

N1-methyladenosine methylation-related metabolic genes signature and subtypes for predicting prognosis and immune microenvironment in osteosarcoma

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