Wild-Type Isocitrate Dehydrogenase 1 Over-Expression is Related to Cancer Stem Cells Survival in Lung Adenocarcinoma

Al-Amodi, Hiba S.; Nabih, Enas Samir; Kamel, Hala F. M.; Sayed, Mohamed Ali El; Dwedar, Ibrahim

doi:10.1080/07357907.2018.1445262

Cited by 9 publications

(8 citation statements)

References 17 publications

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“…On the other hand, IDH1 was found overexpressed in numerous cancers. Importantly, several studies indicate that IDH1 overexpression correlates with poor OS in the non-small cell lung carcinoma (NSCLC) patients adenocarcinoma and squamous cell carcinomas [62,63,64,65]. It has been demonstrated that shRNAs targeting IDH1 decreased in vitro and in vivo growth of NSCLC cell lines [62].…”

Section: Overexpression Of Wild-type Idh1 In Cancersmentioning

confidence: 99%

Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Bergaggio

Piva

2019

Cancers

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Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we summarized findings addressing the impact of IDH mutants in rare pathologies and focused on the relevance of non-mutated IDH enzymes in tumors. Several pieces of evidence suggest that the enzymatic inhibition of IDHs may have therapeutic potentials also in wild-type IDH cancers. Moreover, IDHs inhibition could enhance the efficacy of canonical cancer therapies, such as chemotherapy, target therapy, and radiotherapy. However, further studies are required to elucidate whether IDH proteins are diagnostic/prognostic markers, instrumental for tumor initiation and maintenance, and could be exploited as targets for anticancer therapy. The development of wild-type IDH inhibitors is expected to improve our understanding of a potential non-oncogenic addition to IDH1/2 activities and to fully address their applicability in combination with other therapies.

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Section: Overexpression Of Wild-type Idh1 In Cancersmentioning

confidence: 99%

Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Bergaggio

Piva

2019

Cancers

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“…Although wild-type IDH1 has had much less attention compared to the research on glioma with IDH1 mutation, several studies have revealed that wild-type IDH1 is overexpressed in several types of cancers, including non-small cell lung carcinoma (NSCLC) (17,18), pancreatic adenocarcinoma (PDAC) (19), and primary glioblastoma (20,21). Importantly, these studies show that IDH1 is overexpressed in over 60% of primary glioblastoma patients and is correlated with poor overall survival.…”

Section: Wild-type Idh1 Is Overexpressed In Many Primary Glioblastomamentioning

confidence: 99%

Emerging Roles of Wild-type and Mutant IDH1 in Growth, Metabolism and Therapeutics of Glioma

Garrett¹,

Fujii

Osaka

et al. 2021

Gliomas

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Glioblastoma is one of the most devastating human malignancies and is categorized into primary and secondary glioblastoma subtypes that develop through different genetic pathways. Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key enzymes linking cellular metabolism to epigenetic regulation and redox states. Hot spot mutations of IDH1 is early and frequent genetic alterations in secondary glioblastoma as well as in grade II and III glioma and represent a major biomarker with diagnostic, prognostic, and predictive implications. Mutant IDH proteins acquire neomorphic enzymatic activity to produce D-2hydroxyglutarate, a putative oncometabolite that could induce epigenetic changes

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“…Indeed, a recent study by Su et al highlighted that IDH1 wt (not the mutated form IDH1 R132C ) promotes cell proliferation, invasion and migration in iCCA cell lines by regulation of αKG and NADPH levels [138]. These results are not surprising because over recent years it has emerged that an aberrant expression of non-mutated IDH1 in numerous cancers (e.g., non-small cell lung carcinoma, squamous cell lung cancer, pancreatic ductal adenocarcinoma, primary glioblastoma) [139][140][141][142] correlates with therapy resistance, an aggressive phenotype and poor prognosis [141,[143][144][145]. The biological consequences of IDH1 up-regulation are ascribable to the central role of this enzyme in the regulation of both metabolic and epigenetic processes.…”

Section: Future Perspectives Of Idh1 Inhibitors Use In Intrahepatic Cmentioning

confidence: 99%

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

et al. 2020

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Cholangiocarcinoma is a primary malignancy of the biliary tract characterized by late and unspecific symptoms, unfavorable prognosis, and few treatment options. The advent of next-generation sequencing has revealed potential targetable or actionable molecular alterations in biliary tumors. Among several identified genetic alterations, the IDH1 mutation is arousing interest due to its role in epigenetic and metabolic remodeling. Indeed, some IDH1 point mutations induce widespread epigenetic alterations by means of a gain-of-function of the enzyme, which becomes able to produce the oncometabolite 2-hydroxyglutarate, with inhibitory activity on α-ketoglutarate-dependent enzymes, such as DNA and histone demethylases. Thus, its accumulation produces changes in the expression of several key genes involved in cell differentiation and survival. At present, small-molecule inhibitors of IDH1 mutated enzyme are under investigation in preclinical and clinical phases as promising innovative treatments for IDH1-mutated intrahepatic cholangiocarcinomas. This review examines the molecular rationale and the results of preclinical and early-phase studies on novel pharmacological agents targeting mutant IDH1 in cholangiocarcinoma patients. Contextually, it will offer a starting point for discussion on combined therapies with metabolic and epigenetic drugs, to provide molecular support to target the interplay between metabolism and epigenetics, two hallmarks of cancer onset and progression.

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Wild-Type Isocitrate Dehydrogenase 1 Over-Expression is Related to Cancer Stem Cells Survival in Lung Adenocarcinoma

Cited by 9 publications

References 17 publications

Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy

Emerging Roles of Wild-type and Mutant IDH1 in Growth, Metabolism and Therapeutics of Glioma

IDH1 Targeting as a New Potential Option for Intrahepatic Cholangiocarcinoma Treatment—Current State and Future Perspectives

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