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| Gene | IDH1 |
| Variant | R132H |
| Impact List | missense |
| Protein Effect | gain of function |
| Gene Variant Descriptions | IDH1 R132H lies within the active site of the Idh1 protein (PMID: 19228619). R132H results in decreased conversion of isocitrate to alpha-ketoglutarate by Idh1, but also confers a gain of function to Idh1, as indicated by increased conversion of alpha-ketoglutarate to the onco-metabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture and in vitro assays, and is associated with increased 2HG levels in patient samples (PMID: 19935646, PMID: 23731180). |
| Associated Drug Resistance | |
| Category Variants Paths |
IDH1 mutant IDH1 act mut IDH1 R132H IDH1 mutant IDH1 R132X IDH1 R132H |
| Transcript | NM_005896.4 |
| gDNA | chr2:g.208248388C>T |
| cDNA | c.395G>A |
| Protein | p.R132H |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_005896 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282387 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282386 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282387.1 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282386.1 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282387.1 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_005896.4 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_001282386.1 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| NM_005896.3 | chr2:g.208248388C>T | c.395G>A | p.R132H | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| IDH1 R132H | oligodendroglioma | sensitive | Decitabine | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Dacogen (decitabine) decreased colony formation and tumor growth in patient derived xenograft (PDX) models of patient derived oligodendroglioma cells with IDH1 R132H mutations and co-deletion of 1p and 19q (PMID: 24077826). | 24077826 |
| IDH1 R132H | anaplastic astrocytoma | sensitive | Azacitidine | Preclinical | Actionable | In a preclinical study, long-term treatment with Vidaza (azacitidine) resulted in increased cellular differentiation, decreased proliferation, and tumor regression in a patient-derived xenograft (PDX) model of anaplastic astrocytoma harboring IDH1 R132H (PMID: 24077805). | 24077805 |
| IDH1 R132H | colon carcinoma | sensitive | Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, colon carcinoma cells over expressing IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | high grade glioma | sensitive | Talazoparib | Preclinical - Patient cell culture | Actionable | In a preclinical study, patient-derived glioma cells harboring IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | high grade glioma | sensitive | Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, Talzenna (talazoparib) treatment inhibited viability of immortalized astrocytes expressing IDH1 R132H in culture (PMID: 34118569). | 34118569 |
| IDH1 R132H | colorectal cancer | predicted - sensitive | Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, colorectal cancer cells harboring IDH1 R132H were sensitive to treatment with Talzenna (talazoparib) in culture, demonstrating decreased colony formation (PMID: 29339439). | 29339439 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Niraparib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Zejula (niraparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | colon carcinoma | sensitive | Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, colon carcinoma cells over expressing IDH1 R132H demonstrated increased sensitivity to Lynparza (olaparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | high grade glioma | predicted - sensitive | Olaparib | Phase II | Actionable | In a Phase II trial (OLAGLI), Lynparza (olaparib) therapy was well tolerated in high grade glioma patients harboring IDH1 R132 (32/35) or other IDH mutations (3/35), and led to a partial response in 5% (2/35) and stable disease in 37% (14/35) of 35 evaluable patients, median progression-free survival (PFS) of 2.3 mo, median overall survival of 15.9 mo, a median duration of response of 9 mo, and a 6-mo PFS of 31% (11/35) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 2007-2007; NCT03561870). | detail... |
| IDH1 R132H | high grade glioma | predicted - sensitive | Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, Lynparza (olaparib) treatment inhibited viability of a glioma cell line expressing IDH1 R132H in culture (PMID: 34118569). | 34118569 |
| IDH1 R132H | colorectal cancer | predicted - sensitive | Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, colorectal cancer cells harboring IDH1 R132H were sensitive to treatment with Lynparza (olaparib) in culture, demonstrating decreased colony formation (PMID: 29339439). | 29339439 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Lynparza (olaparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Rucaparib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells over expressing IDH1 R132H demonstrated increased sensitivity to Rubraca (rucaparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | colorectal cancer | sensitive | Metformin | Preclinical | Actionable | In a preclinical study, colorectal carcinoma cells expressing IDH1 R132H were sensitive to Glucophage (metformin), resulting in decreased cell proliferation in culture (PMID: 26363012). | 26363012 |
| 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 | high grade glioma | decreased response | Panobinostat | Preclinical - Cell culture | Actionable | In a preclinical study, mouse glioma cells expressing IDH1 R132H were less sensitive to Farydak (panobinostat) compared to IDH1 wild-type cells in culture (PMID: 38334611). | 38334611 |
| IDH1 R132H | cholangiocarcinoma | sensitive | Ivosidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III (ClarIDHy) trial that supported FDA approval, Tibsovo (ivosidenib) treatment significantly improved median progression-free survival (2.7 vs 1.4 mo, HR=0.37, p<0.001) and prolonged median overall survival (10.8 vs 9.7 mo, HR=0.69, p=0.06) compared to placebo in patients with advanced cholangiocarcinoma harboring IDH1 mutations including R132C/H/L/G/S, resulted in favorable objective response rate (2%, 3/124 vs 0%, 0/61) and stable disease rate (51% vs 28%) (PMID: 32416072; NCT02989857). | detail... 32416072 detail... |
| IDH1 R132H | acute myeloid leukemia | sensitive | Ivosidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I trial that supported FDA approval, Tibsovo (ivosidenib) treatment resulted in complete remission (CR) in 21.6% (27/125), CR with partial hematological recovery (CRh) in 8.8% (11/125), and overall response (OR) in 41.6% (52/125) of patients with relapsed or refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132C/G/H/L/S) as detected by an FDA-approved test (PMID: 29860938; NCT02074839). | 29860938 detail... detail... |
| IDH1 R132H | acute myeloid leukemia | sensitive | Ivosidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I trial that supported FDA approval, Tibsovo (ivosidenib) treatment resulted in complete remission (CR) in 28.6% (8/28), CR with partial hematological recovery (CRh) in 14.3% (4/28) of patients age 75 or older with untreated acute myeloid leukemia harboring a susceptible IDH1 mutation (R132C/G/H/L/S) as detected by an FDA-approved test, with a median treatment duration of 4.3 months (PMID: 29860938; NCT02074839). | 29860938 detail... detail... |
| IDH1 R132H | myelodysplastic syndrome | sensitive | Ivosidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I trial that supported FDA approval, Tibsovo (ivosidenib) was tolerated and resulted in a complete response (CR) in 44% (7/16), partial response (PR) in 6% (1/16), and marrow CR in 31% (5/16) of patients with relapsed or refractory myelodysplastic syndrome harboring a susceptible IDH1 mutation (R132C/G/H/L/S) as detected by an FDA-approved test, with a hematologic improvement in >/=1 lineages achieved by 69% (11/16) of patients (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 7053; NCT02074839). | detail... detail... detail... |
| IDH1 R132H | low grade glioma | predicted - sensitive | Ivosidenib | Phase I | Actionable | In a Phase I trial, low grade glioma patients with an IDH1 mutation (n=66; R132H=57, R132C/G/S=1 each, R132X=5) treated with Tibsovo (ivosidenib) demonstrated an overall response rate of 2.9% (1/35, 1 partial response) and stable disease in 85.7% (30/35) of patients with a non-enhancing glioma versus no responses and stable disease in 45.2% (14/31) of patients with an enhancing glioma, and led to a median progression-free survival of 13.6 months and 1.4 months, respectively (PMID: 32530764; NCT02073994). | 32530764 |
| IDH1 R132H | high grade glioma | not applicable | N/A | Guideline | Diagnostic | IDH1 R132H is diagnostic and aids in the diagnosis of gliomas (NCCN.org). | detail... |
| IDH1 R132H | high grade glioma | sensitive | AGI-5198 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, AGI-5198 inhibited growth of a glioma cell line harboring IDH1 R132H in culture and in xenograft models (PMID: 23558169). | 23558169 |
| 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 | Advanced Solid Tumor | sensitive | Berzosertib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing IDH1 R132H demonstrated increased sensitivity to Berzosertib (VX-970)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Ceralasertib | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with Ceralasertib (AZD6738) resulted in decreased survival in cell lines expressing IDH1 R132H in culture (PMID: 34027408). | 34027408 |
| IDH1 R132H | high grade glioma | predicted - sensitive | Vorasidenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Voranigo (vorasidenib) treatment decreased brain tumor 2HG levels in an orthotopic glioma cell line xenograft model harboring IDH1 R132H (Mol Cancer Ther Jan 1 2018 (17) (1 Supp) B126). | detail... |
| IDH1 R132H | glioblastoma | sensitive | Temozolomide + Vandetanib | Phase II | Actionable | In a Phase II trial, Caprelsa (vandetanib), in combination with Temodar (temozolomide) and radiation therapy, demonstrated a significant increase in PFS and OS in glioblastoma patients harboring IDH1 R132H compared to glioblastoma patients without IDH1 R132H (PMID: 25910950). | 25910950 |
| IDH1 R132H | colorectal cancer | resistant | AGI-5198 + Metformin | Preclinical | Actionable | In a preclinical study, colorectal cancer cells harboring IDH1 R132H demonstrated increased cell proliferation when treated with a combination of Glucophage (metformin) and AGI-5198 (PMID: 26363012). | 26363012 |
| IDH1 R132H | colorectal cancer | resistant | AGI-5198 + Radiotherapy | Preclinical | Actionable | In a preclinical study, colorectal cancer cells expressing IDH1 R132H were resistant to radiotherapy when treated with AGI-5198 (PMID: 26363012). | 26363012 |
| IDH1 R132H | acute myeloid leukemia | sensitive | Azacitidine + Ivosidenib | Phase Ib/II | Actionable | In a Phase Ib trial, Tibsovo (ivosidenib) and Vidaza (azacitidine) combination treatment demonstrated a favorable safety profile and resulted in an objective response rate (ORR) of 78.3% (18/23, 14 complete remission) and a 12-month overall survival probability of 82% in patients with newly diagnosed acute myeloid leukemia harboring IDH1 R132H (n=4), R132C (n=16), or R132L (n=3) mutations (PMID: 33119479; NCT02677922). | 33119479 |
| IDH1 R132H | acute myeloid leukemia | sensitive | Azacitidine + Ivosidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (AGILE) that supported FDA approval, Tibsovo (ivosidenib) and Vidaza (azacitidine) combination therapy significantly improved event-free survival (HR 0.33, p=0.002) and median overall survival (24.0 vs 7.9 mo, HR 0.44, p=0.001) compared to Vidaza (azacitidine) plus placebo in patients with newly diagnosed acute myeloid leukemia harboring IDH1 mutations including R132C/H/G/L/S (PMID: 35443108; NCT03173248). | 35443108 detail... detail... |
| IDH1 R132H | acute myeloid leukemia | sensitive | Olutasidenib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial (Study 2102-HEM-101) that supported FDA approval, Rezlidhia (olutasidenib) treatment resulted in an objective response rate of 46% (57/123, 37 complete remission (CR), 4 CR with partial hematologic recovery, 14 CR with incomplete recovery, 1 morphologic leukemia-free state, 1 partial response) in patients with relapsed/refractory acute myeloid leukemia harboring a susceptible IDH1 mutation (R132H/C/G/L/S) (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7006; NCT02719574). | detail... detail... detail... |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Ceralasertib + Olaparib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Lynparza (olaparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell survival compared to Ceralasterib (AZD6738) alone in cells expressing IDH1 R132H in culture, and a longer delay in tumor growth in cell line xenograft models (PMID: 34027408). | 34027408 |
| IDH1 R132H | high grade glioma | sensitive | BPTES | Preclinical - Cell culture | Actionable | In a preclinical study, a glioma cell line expressing IDH1 R132H demonstrated increased sensitivity to growth inhibition by BPTES compared to a cell line expressing wild-type IDH1 in culture (PMID: 21045145). | 21045145 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Cisplatin + Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, Talzenna (talazoparib) and Cisplatin synergistically inhibited growth of transformed cells over expressing IDH1 R132H in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | Advanced Solid Tumor | decreased response | AGI-5198 + Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, AGI-5198 reverted the sensitivity of transformed cells over expressing IDH1 R132H to Talzenna (talazoparib)-induced growth inhibition in culture (PMID: 28148839). | 28148839 |
| IDH1 R132H | acute myeloid leukemia | sensitive | BAY1436032 | Preclinical - Patient cell culture | Actionable | In a preclinical study, BAY1436032 decreased (R)-2-hydroxyglutarate (R-2HG) levels, and inhibited growth and increased differentiation of patient-derived acute myeloid leukemia cells harboring IDH1 R132H in culture (PMID: 28232670). | 28232670 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Elimusertib | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with Elimusertib (BAY1895344) resulted in decreased survival in cell lines expressing IDH1 R132H in culture (PMID: 34027408). | 34027408 |
| IDH1 R132H | glioblastoma | sensitive | DS-1001b | Preclinical - Pdx | Actionable | In a preclinical study, treatment with DS-1001b inhibited subcutaneous and intracranial tumor growth in a patient-derived xenograft (PDX) model of glioblastoma harboring IDH1 R132H, and also demonstrated reduced levels of the oncometabolite 2-hydroxyglutarate (2-HG) within tumors and plasma and increased expression of the astrocyte differentiation marker glial fibrillary acidic protein in tumor cells (PMID: 31727689). | 31727689 |
| IDH1 R132H | Advanced Solid Tumor | predicted - sensitive | DS-1001b | Preclinical - Biochemical | Actionable | In a preclinical study, DS-1001b inhibited IDH1 R132H enzymatic activity in an in vitro assay, and inhibited production of the oncometabolite 2-hydroxyglutarate (2-HG) in transformed human cells expressing IDH1 R132H in culture (PMID: 31727689). | 31727689 |
| IDH1 R132H | malignant astrocytoma | predicted - sensitive | IDH1 R132H peptide vaccine | Phase I | Actionable | In a Phase I trial (NOA-16), treatment with IDH1 R132H peptide vaccine demonstrated safety in patients with malignant astrocytoma harboring IDH1 R132H and led to stable disease in 87.5% (28/32) of patients (J Clin Oncol 36, no. 15_suppl (May 20, 2018) 2001; NCT02454634). | detail... |
| 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 | 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 |
| IDH1 R132H | high grade glioma | sensitive | Olaparib + Radiotherapy | Preclinical - Cell culture | Actionable | In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of immortalized astrocytes expressing IDH1 R132H to radiation therapy in culture, resulting in increased cell death and decreased colony formation compared to radiation therapy alone (PMID: 32494639). | 32494639 |
| IDH1 R132H | intrahepatic cholangiocarcinoma | sensitive | Olaparib + Radiotherapy | Preclinical - Cell line xenograft | Actionable | In a preclinical study, treatment with Lynparza (olaparib) enhanced the sensitivity of an intrahepatic cholangiocarcinoma cell line expressing IDH1 R132H to radiation therapy, resulting in decreased survival in culture and delayed tumor growth and increased survival compared to radiation therapy alone in a cell line xenograft model, with a median overall survival of 60 days vs 47 days, respectively (PMID: 32494639). | 32494639 |
| IDH1 R132H | Advanced Solid Tumor | predicted - sensitive | HMPL-306 | Preclinical - Biochemical | Actionable | In a preclinical study, HMPL-306 inhibited the enzymatic activity of IDH1 R132H in a fluorescence-based assay (Cancer Res (2023) 83 (7_Supplement): 543). | detail... |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Elimusertib + Olaparib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Lynparza (olaparib) and Elimusertib (BAY1895344) resulted in a greater decrease in cell survival compared to BAY1895344 alone in cells expressing IDH1 R132H in culture (PMID: 34027408). | 34027408 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Ceralasertib + Niraparib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Zejula (niraparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in cells expressing IDH1 R132H in culture (PMID: 34027408). | 34027408 |
| IDH1 R132H | Advanced Solid Tumor | sensitive | Ceralasertib + Talazoparib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Talzenna (talazoparib) and Ceralasertib (AZD6738) resulted in a greater decrease in cell viability compared to Ceralasertib (AZD6738) alone in cells expressing IDH1 R132H in culture (PMID: 34027408). | 34027408 |
| IDH1 R132H | high grade glioma | sensitive | Radiotherapy + Veliparib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, treatment with Veliparib (ABT-888) enhanced sensitivity to radiation therapy in immortalized astrocytes expressing IDH1 R132H in culture, resulting in greater decreased colony formation, and in a glioma cell line xenograft model, resulting in both increased tumor regression and survival compared to radiation therapy alone, with a median overall survival of 66 days vs 22 days, respectively (PMID: 32494639). | 32494639 |
| IDH1 R132H | high grade glioma | sensitive | Pamiparib + Radiotherapy | Preclinical - Cell line xenograft | Actionable | In a preclinical study, treatment with Pamiparib (BGB-290) enhanced the sensitivity of a glioma cell line expressing IDH1 R132H to radiation therapy, resulting in a reduction in tumor volume and increased survival compared to radiation therapy alone in a cell line xenograft model (PMID: 32494639). | 32494639 |
| IDH1 R132H | high grade glioma | sensitive | Panobinostat + Tazemetostat | Preclinical - Cell culture | Actionable | In a preclinical study, cotreatment with Tazverik (tazemetostat) sensitized mouse glioma cells expressing IDH1 R132H to Farydak (panobinostat) in culture, resulting in synergistic inhibition of cell viability (PMID: 38334611). | 38334611 |