Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer

Lee, Hyun-Min; Cai, Feng; Kelekar, Neil; Velupally, Nipun; Kim, Jiyeon

doi:10.3390/cells11010176

Cited by 11 publications

(12 citation statements)

References 32 publications

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“…Lee et al. ( 17 ) showed that targeted therapy against PGM3 could be a therapeutic strategy for KRAS/LKB1 co-mutant lung cancer, validating the tumor-promoting effect of high expression of PGM3.…”

Section: Discussionmentioning

confidence: 98%

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Meta-analysis of the effect of PGM on survival prognosis of tumor patients

Zheng

Bai

Shen³

et al. 2022

Front. Oncol.

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ObjectiveA systematic evaluation of the impact of phosphoglucose translocase PGM on the survival prognosis of tumor patients was conducted to understand its impact on tumors so as to improve the quality of survival and to find effective therapeutic targets for tumor patients.MethodsThe following were searched in the databases China National Knowledge Infrastructure (CNKI), Wanfang, Wipu, PubMed, EMBASE, ScienceDirect, Web of Science, and Cochrane Library: “PGM1”, “PGM2”, “PGM3”, “PGM4”, and “PGM5” as Chinese keywords and “PGM1”, “PGM2”, “PGM3”, “PGM4”, “PGM5”, “PGM1 cancer”, “PGM2 cancer”, “PGM3 cancer”, “PGM4 cancer”, “PGM5 cancer”, and “phosphoglucomutase”. Relevant studies published from the database establishment to April 2022 were collected. Studies that met the inclusion criteria were extracted and evaluated for quality with reference to the Cochrane 5.1.0 systematic evaluation method, and quality assessment was performed using RevMan 5.3 software.ResultsThe final results of nine articles and 10 studies with a total of 3,806 patients were included, including 272 patients in the PGM1 group, 541 patients in the PGM2 group, 1,775 patients in the PGM3 group, and 1,585 patients in the PGM5 group. Results of the meta-analysis: after determining the results of the nine articles, it was found that the difference was statistically significant with a p-value <0.05 (hazard ratio (HR) = 0.89, 95% CI 0.69–1.09, p = 0.000). To find the sources of heterogeneity, the remaining eight papers were tested after removing the highly sensitive literature, and the results showed I2 = 26.5%, p < 0.001, a statistically significant difference. The HR for high expression of PGM1 and PGM2 and PGM5 was <1, while the HR for high expression of PGM3 was >1.ConclusionAlthough PGM1, PGM2, PGM3, and PGM5 are enzymes of the same family, their effects on tumors are different. High expression of PGM1, PGM2, and PGM5 can effectively prolong the overall survival of patients. In contrast, high expression of PGM3 reduced the overall survival of patients. This study of PGM family enzymes can assist in subsequent tumor diagnosis, treatment, and prognostic assessment.

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Section: Discussionmentioning

confidence: 98%

“…PGM3 is a N-acetylglucosamine triphosphatase involved in the biosynthesis of aminoalanine, which exerts anticancer effects (25). Lee et al (17) showed that targeted therapy against PGM3 could be a therapeutic strategy for KRAS/LKB1 co-mutant lung cancer, validating the tumor-promoting effect of high expression of PGM3.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of the effect of PGM on survival prognosis of tumor patients

Zheng

Bai

Shen³

et al. 2022

Front. Oncol.

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“…Our in silico study suggested that targeting HBP enzymes will be a potentially feasible approach to treat UBC cells in future. Actually, targeting GFPT2 by azaserine and targeting PGM3 by FR054 can specifically inhibit KRAS/LKB1 combined mutant lung adenocarcinoma cells, respectively ( Kim et al, 2020 ; Lee et al, 2022 ). In addition, targeting GFPT1 by DON blocked the PCK1-loss induced O-GlcNAclyation and liver cancer aggressiveness ( Xiang et al, 2021 ), and enhanced anti-PD-1 immunotherapy effects in pancreatic cancer ( Sharma et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of hexosamine biosynthesis pathway as a novel prognostic signature and its correlation with immune infiltration in bladder cancer

Cui

Feng

Liu

et al. 2022

Front. Mol. Biosci.

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Background: Urinary bladder cancer (UBC) is one of the common urological malignancies, lacking reliable biomarkers to predict clinical outcomes in UBC patients. Thus, it is needed to identify the novel diagnostic/prognostic biomarkers to stratify the high-risk UBC patients. As a shunt pathway of glycolysis, the hexosamine biosynthesis pathway (HBP) has been implicated in carcinogenesis. However, its prognostic value in UBC remains unclear.Methods: The RNA sequencing and mRNA microarray datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus databases. The expression levels of five HBP genes were analyzed in normal and UBC samples, and their associations with stage, grade and survival were plotted. The performance of HBP risk group was evaluated by receiver-operating characteristics (ROC) curve. The HBP signature was generated by Gene Set Variation Analysis (GSVA) and its association with clinicopathological parameters and survival were analyzed. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were carried out to examine the potential biological functions of HBP using DAVID online tool. The infiltration estimation fraction of immune cells was performed using CIBERSORT-ABS algorithm. Gene set enrichment analysis (GSEA) was used to explore the potential function of HBP in tumor immunoregulation.Results: Four HBP genes were upregulated in UBCs compared to normal tissues in TCGA-BLCA dataset. The upregulation of all five HBP genes was significantly associated with tumor grade and stage of UBC in three independent UBC datasets. The expression of HBP genes predicted poor clinical outcomes in UBC patients in both TCGA-BLCA and GSE13507 datasets. The high-risk group based on HBP genes showed a poor prognosis. Furthermore, HBP signature was positively associated with tumor grade and stage in TCGA-BLCA dataset and with tumor grade, stage, distal metastasis and poor survival in GSE13507 dataset. Interestingly, high-HBP signature group exhibited a high infiltration of immune cells, particularly the macrophage population.Conclusion: We identified that HBP was a promising prognostic biomarker in UBC patients and strongly associated with immune infiltration.

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“…It has also been found that regenerating family member (REG4) is highly expressed in KRAS-mutant lung adenocarcinoma, and that silencing REG4 can inhibit cancer cell proliferation and genesis, making it a potential therapeutic target [ 130 ]. A study finds that the inhibition of phosphoglucomutase 3 (PGM3) reduces the growth of KRAS/LKB1 co-mutant lung tumors in both in vitro and in vivo settings, suggesting the potential for PGM3 targeted therapy in the KRAS-mutant population [ 131 ].…”

Section: Advances In Drug Resistance and Oncological Mechanisms Of Kr...mentioning

confidence: 99%

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

Yang

Zhang

Huang

et al. 2023

JCM

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Kristen rat sarcoma (KRAS) gene is one of the most common mutated oncogenes in solid tumors. Yet, KRAS inhibitors did not follow suit with the development of targeted therapy, for the structure of KRAS has been considered as being implausible to target for decades. Chemotherapy was the initial recommended therapy for KRAS-mutant cancer patients, which was then replaced by or combined with immunotherapy. KRAS G12C inhibitors became the most recent breakthrough in targeted therapy, with Sotorasib being approved by the Food and Drug Administration (FDA) based on its significant efficacy in multiple clinical studies. However, the subtypes of the KRAS mutations are complex, and the development of inhibitors targeting non-G12C subtypes is still at a relatively early stage. In addition, the monotherapy of KRAS inhibitors has accumulated possible resistance, acquiring the exploration of combination therapies or next-generation KRAS inhibitors. Thus, other non-target, conventional therapies have also been considered as being promising. Here in this review, we went through the characteristics of KRAS mutations in cancer patients, and the prognostic effect that it poses on different therapies and advanced therapeutic strategy, as well as cutting-edge research on the mechanisms of drug resistance, tumor development, and the immune microenvironment.

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Targeting PGM3 as a Novel Therapeutic Strategy in KRAS/LKB1 Co-Mutant Lung Cancer

Cited by 11 publications

References 32 publications

Meta-analysis of the effect of PGM on survival prognosis of tumor patients

Meta-analysis of the effect of PGM on survival prognosis of tumor patients

Identification of hexosamine biosynthesis pathway as a novel prognostic signature and its correlation with immune infiltration in bladder cancer

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

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