Reference Detail

Ref Type

Journal Article

PMID

(31151327)

Authors

Kim GH, Choi SY, Oh TI, Kan SY, Kang H, Lee S, Oh T, Ko HM, Lim JH

Title

IDH1R132H Causes Resistance to HDAC Inhibitors by Increasing NANOG in Glioblastoma Cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
International journal of molecular sciences	20	11	2019 May 31		Int J Mol Sci

URL

Abstract Text

The R132H mutation in isocitrate dehydrogenase 1 (IDH1R132H) is commonly observed and associated with better survival in glioblastoma multiforme (GBM), a malignant brain tumor. However, the functional role of IDH1R132H as a molecular target for GBM treatment is not completely understood. In this study, we found that the overexpression of IDH1R132H suppresses cell growth, cell cycle progression and motility in U87MG glioblastoma cells. Based on cell viability and apoptosis assays, we found that IDH1R132H-overexpressing U87MG and U373MG cells are resistant to the anti-cancer effect of histone deacetylase inhibitors (HDACi), such as trichostatin A (TSA), vorinostat (SAHA), and valproic acid. Octyl-(R)-2-hydroxyglutarate (Octyl-2HG), which is a membrane-permeable precursor form of the oncometabolite (R)-2-hydroxyglutarate (R-2HG) produced in IDH1-mutant tumor cells, significantly increased HDACi resistance in glioblastoma cells. Mechanistically, IDH1R132H and Octyl-2HG enhanced the promoter activation of NANOG via increased H3K4-3Me, consequently increasing NANOG mRNA and protein expression. Indeed, HDACi resistance was attenuated in IDH1R132H-expressing glioblastoma cells by the suppression of NANOG using small interfering RNAs. Furthermore, we found that AGI-5198, a selective inhibitor of IDH1R132H, significantly attenuates HDACi resistance and NANOG expression IDH1R132H-expressing glioblastoma cells. These results suggested that IDH1R132H is a potential molecular target for HDACi-based therapy for GBM.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
AGI-5198	AGI-5198	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
AGI-5198		AG5198\|AGI 5198\|IDH-C35	IDH1 Inhibitor 8	AGI-5198 is a selective inhibitor of mutant forms of IDH1, which decreases production of R-2HG, potentially leading to reduced growth of IDH1-mutant tumor cells (PMID: 23558169, PMID: 26368816, PMID: 31151327).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
IDH1 R132H	glioblastoma	resistant	Valproic acid	Preclinical - Cell culture	Actionable	In a preclinical study, glioblastoma cells expressing IDH1 R132H were resistant to treatment with Valproic Acid in culture, demonstrating increased cell viability (PMID: 31151327).	31151327
IDH1 R132H	glioblastoma	resistant	Vorinostat	Preclinical - Cell culture	Actionable	In a preclinical study, glioblastoma cells expressing IDH1 R132H were resistant to treatment with Zolinza (vorinostat) in culture, demonstrating increased cell viability (PMID: 31151327).	31151327
IDH1 R132H	glioblastoma	predicted - sensitive	AGI-5198 + Trichostatin A	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of AGI-5198 treatment in glioblastoma cells expressing IDH1 R132H led to decreased resistance to Trichostatin (TSA) treatment in culture, resulting in reduced cell viability (PMID: 31151327).	31151327
IDH1 R132H	glioblastoma	resistant	Trichostatin A	Preclinical - Cell culture	Actionable	In a preclinical study, glioblastoma cells expressing IDH1 R132H were resistant to treatment with Trichostatin (TSA) in culture, demonstrating decreased apoptotic activity and increased cell viability (PMID: 31151327).	31151327
IDH1 R132H	glioblastoma	predicted - sensitive	AGI-5198 + Vorinostat	Preclinical - Cell culture	Actionable	In a preclinical study, the addition of AGI-5198 treatment in glioblastoma cells expressing IDH1 R132H led to decreased resistance to Zolinza (vorinostat) treatment in culture, resulting in reduced cell viability (PMID: 31151327).	31151327