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Gene | IDH2 |
Variant | R140Q |
Impact List | missense |
Protein Effect | gain of function |
Gene Variant Descriptions | IDH2 R140Q lies within the substrate binding region of the Idh2 protein (UniProt.org). R140Q confers a gain of function to Idh2, enabling conversion of alpha-ketoglutarate to the onco-metabolite 2HG (R(-)-2-hydroxyglutarate), results in increased 2HG levels in patient samples, and is transforming in cell culture (PMID: 20171147, PMID: 23558173). |
Associated Drug Resistance | |
Category Variants Paths |
IDH2 mutant IDH2 act mut IDH2 R140Q IDH2 mutant IDH2 R140X IDH2 R140Q |
Transcript | NM_002168.4 |
gDNA | chr15:g.90088702C>T |
cDNA | c.419G>A |
Protein | p.R140Q |
Source Database | RefSeq |
Genome Build | GRCh38/hg38 |
Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
---|---|---|---|---|---|
NM_002168.4 | chr15:g.90088702C>T | c.419G>A | p.R140Q | RefSeq | GRCh38/hg38 |
NM_002168.3 | chr15:g.90088702C>T | c.419G>A | p.R140Q | RefSeq | GRCh38/hg38 |
NM_002168 | chr15:g.90088702C>T | c.419G>A | p.R140Q | RefSeq | GRCh38/hg38 |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
IDH2 R140Q | acute myeloid leukemia | sensitive | AGI-6780 | Preclinical | Actionable | In a preclinical study, treatment with AGI-6780 resulted in the differentiation of erythroleukemia and AML cell lines expressing IDH2 R140Q (PMID: 23558173). | 23558173 |
IDH2 R140Q | acute myeloid leukemia | sensitive | Enasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I/II trial that supported FDA approval, Idhifa (enasidenib) treatment resulted in an overall response rate of 40.3% (71/176) with a median response duration of 5.8 months, complete remission in 19.3% (34/176), and stable disease in 48.3% (85/176) of acute myeloid leukemia patients harboring IDH2 mutations (PMID: 28588020; NCT01915498) and IDH2 R140Q is on the companion diagnostic. | detail... detail... 28588020 |
IDH2 R140Q | acute myeloid leukemia | sensitive | Enasidenib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Enasidenib (AG-221) treatment reduced 2-hydroxyglutarate (2HG) levels and induced differentiation of leukemic blasts from acute myeloid leukemia (AML) patients harboring IDH2 R140Q in culture, and decreased 2HG levels and blast percentage and improved survival relative to Cytosar-U (cytarabine) treatment in IDH2 R140Q-mutant primary AML xenograft models (PMID: 28193778). | 28193778 |
IDH2 R140Q | glioblastoma | predicted - sensitive | Enasidenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Enasidenib (AG-221) decreased 2-hydroxyglutarate (2HG) levels in a glioblastoma cell line expressing IDH2 R140Q in culture and in xenograft models (PMID: 28193778). | 28193778 |
IDH2 R140Q | high grade glioma | predicted - sensitive | Vorasidenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Voranigo (vorasidenib) treatment decreased tumor 2HG levels in a glioma cell line xenograft model harboring IDH2 R140Q (Mol Cancer Ther Jan 1 2018 (17) (1 Supp) B126). | detail... |
IDH2 R140Q | myelodysplastic syndrome | not applicable | N/A | Guideline | Prognostic | IDH2 R140Q is associated with a poor prognosis in patients with myelodysplastic syndrome (NCCN.org). | detail... |
IDH2 R140Q | leukemia | sensitive | TETi76 | Preclinical - Cell culture | Actionable | In a preclinical study, TETi76 treatment decreased viability of a leukemia cell line expressing IDH2 R140Q in culture (PMID: 33681816). | 33681816 |
IDH2 R140Q | hematologic cancer | predicted - sensitive | SH1573 | Preclinical - Cell culture | Actionable | In a preclinical study, SH1573 treatment decreased 2-HG levels and increased differentiation of a tumor cell line expressing IDH2 R140Q in culture (PMID: 34221866). | 34221866 |
IDH2 R140Q | high grade glioma | sensitive | TQ05310 | Preclinical - Cell culture | Actionable | In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in a glioma cell line expressing IDH2 R140Q in culture (PMID: 31361380). | 31361380 |
IDH2 R140Q | acute myeloid leukemia | sensitive | TQ05310 | Preclinical - Cell culture | Actionable | In a preclinical study, TQ05310 treatment decreased 2-HG levels and increased differentiation in an acute myeloid leukemia cell line expressing IDH2 R140Q in culture (PMID: 31361380). | 31361380 |
IDH2 R140Q | Advanced Solid Tumor | predicted - sensitive | HMPL-306 | Preclinical - Biochemical | Actionable | In a preclinical study, HMPL-306 inhibited the enzymatic activity of IDH2 R140Q in a fluorescence-based assay (Cancer Res (2023) 83 (7_Supplement): 543). | detail... |
IDH2 R140Q | acute myeloid leukemia | predicted - sensitive | Enasidenib + Venetoclax | Phase Ib/II | Actionable | In a Phase Ib/II trial, Idhifa (enasidenib) plus Venclexta (venetoclax) was well tolerated and demonstrated activity in patients with relapsed or refractory acute myeloid leukemia harboring IDH2 R140Q (15/27) or IDH2 R172K/W (11/27), resulting in an overall response rate (ORR) of 70% (16/23), with complete remission (CR) in 57% (13/23) of evaluable patients, and an ORR of 55% (6/11) and a CR rate of 45% (5/11) in patients harboring IDH2 R140Q (Blood (2023) 142 (Supplement 1): 159; NCT04092179). | detail... |