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Ref Type Journal Article
PMID (30249606)
Authors Avellaneda Matteo D, Wells GA, Luna LA, Grunseth AJ, Zagnitko O, Scott DA, Hoang A, Luthra A, Swairjo MA, Schiffer JM, Sohl CD
Title Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants.
Journal Vol Issue Date Pages Journal Short Title
The Biochemical journal 475 20 2018 Oct 22 3221-3238 Biochem J
URL
Abstract Text Mutations in isocitrate dehydrogenase 1 (IDH1) drive most low-grade gliomas and secondary glioblastomas and many chondrosarcomas and acute myeloid leukemia cases. Most tumor-relevant IDH1 mutations are deficient in the normal oxidization of isocitrate to α-ketoglutarate (αKG), but gain the neomorphic activity of reducing αKG to D-2-hydroxyglutarate (D2HG), which drives tumorigenesis. We found previously that IDH1 mutants exhibit one of two reactivities: deficient αKG and moderate D2HG production (including commonly observed R132H and R132C) or moderate αKG and high D2HG production (R132Q). Here, we identify a third type of reactivity, deficient αKG and high D2HG production (R132L). We show that R132Q IDH1 has unique structural features and distinct reactivities towards mutant IDH1 inhibitors. Biochemical and cell-based assays demonstrate that while most tumor-relevant mutations were effectively inhibited by mutant IDH1 inhibitors, R132Q IDH1 had up to a 16 300-fold increase in IC50 versus R132H IDH1. Only compounds that inhibited wild-type (WT) IDH1 were effective against R132Q. This suggests that patients with a R132Q mutation may have a poor response to mutant IDH1 therapies. Molecular dynamics simulations revealed that near the NADP+/NADPH-binding site in R132Q IDH1, a pair of α-helices switches between conformations that are more wild-type-like or more mutant-like, highlighting mechanisms for preserved WT activity. Dihedral angle changes in the dimer interface and buried surface area charges highlight possible mechanisms for loss of inhibitor affinity against R132Q. This work provides a platform for predicting a patient's therapeutic response and identifies a potential resistance mutation that may arise upon treatment with mutant IDH inhibitors.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
IDH1 R132Q missense gain of function IDH1 R132Q lies within the active site of the Idh1 protein (PMID: 19228619). R132Q 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 (PMID: 30249606, PMID: 28330869).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132H Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132H in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132Q Advanced Solid Tumor predicted - sensitive GSK864 Preclinical - Biochemical Actionable In a preclinical study, GSK864 inhibited the activity of IDH1 R132Q in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132L Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132L in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132H Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132H in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132G Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132G in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132V Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132V in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132V Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132V in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132Q Advanced Solid Tumor predicted - resistant AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 treatment did not inhibit the activity of IDH1 R132Q in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132Q Advanced Solid Tumor predicted - resistant ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 treatment did not inhibit the activity of IDH1 R132Q in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132H Advanced Solid Tumor predicted - sensitive GSK864 Preclinical - Biochemical Actionable In a preclinical study, GSK864 inhibited the activity of IDH1 R132H in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132L Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132L in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132S Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132S in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132G Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132G in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132C Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132C in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132S Advanced Solid Tumor predicted - sensitive ML309 Preclinical - Biochemical Actionable In a preclinical study, ML309 inhibited the activity of IDH1 R132S in an in vitro assay (PMID: 30249606). 30249606
IDH1 R132C Advanced Solid Tumor predicted - sensitive AGI-5198 Preclinical - Biochemical Actionable In a preclinical study, AGI-5198 inhibited the activity of IDH1 R132C in an in vitro assay (PMID: 30249606). 30249606