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Updated: Feb 4, 2026
Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
Inhibitor potency varies widely among tumor-relevant human isocitrate dehydrogenase 1 mutants
Diego Avellaneda Matteo1, Grace A Wells1, Lucas A Luna1
1Department of Chemistry and Biochemistry, San Diego State University, San Diego, CA, U.S.A.
Abstract:
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.
Insights
A new IDH1 mutation (R132L) was discovered, exhibiting unique reactivity. The R132Q mutant IDH1 shows resistance to inhibitors, potentially impacting cancer therapy response.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Isocitrate dehydrogenase 1 (IDH1) mutations are key drivers in various cancers, including gliomas and acute myeloid leukemia.
- Most IDH1 mutations lead to deficient α-ketoglutarate (αKG) oxidation and neomorphic D-2-hydroxyglutarate (D2HG) production, promoting tumorigenesis.
- Previously identified IDH1 mutants show two distinct reactivity patterns regarding αKG and D2HG production.
Purpose of the Study:
- To characterize a newly identified IDH1 mutation, R132L, with a distinct reactivity profile.
- To investigate the biochemical and structural basis for the differential response of IDH1 mutants to targeted inhibitors.
- To assess the therapeutic implications of the R132Q mutation's resistance to mutant IDH1 inhibitors.
Main Methods:
- Biochemical assays to measure enzyme activity and inhibitor IC50 values.
- Cell-based assays to evaluate cellular responses to IDH1 mutations and inhibitors.
- Molecular dynamics simulations to analyze structural changes and binding site interactions.
Main Results:
- A third IDH1 mutant reactivity was identified: R132L exhibits deficient αKG and high D2HG production.
- The R132Q IDH1 mutant displayed significantly reduced sensitivity (up to 16,300-fold higher IC50) to mutant IDH1 inhibitors compared to R132H.
- Only inhibitors targeting wild-type (WT) IDH1 were effective against the R132Q mutant.
- Molecular dynamics revealed conformational flexibility in the NADP+/NADPH-binding site and altered dimer interface in R132Q, explaining preserved WT activity and reduced inhibitor affinity.
Conclusions:
- The R132Q IDH1 mutation confers resistance to current mutant IDH1 inhibitors, suggesting potential therapeutic challenges for patients with this mutation.
- Structural insights into R132Q IDH1 provide a basis for predicting patient response to therapy and understanding resistance mechanisms.
- This study highlights the importance of characterizing diverse IDH1 mutant reactivities for developing effective and personalized cancer treatments.
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