An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells

By D. Rohle, Janeta Popovici-Muller, N. Palaskas, Şevin Turcan, C. Grommes, Carl Campos, J. Tsoi, O. Clark, Barbara Oldrini, Evangelia Komisopoulou and 18 more. Science, 2013

1,105 citations recorded by the source corpus.

IDHology Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis). F. Wang et al. (p. 622, published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626, published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation. A small molecule that inhibits a mutant enzyme in tumors slows malignant growth by inducing cancer cell differentiation. [Also see Perspective by Kim and DeBerardinis] The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/29dad94ec38f6e966c2f0229cad8443f21315420

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Citations in the corpus

Tumor evolution of glioma intrinsic gene expression subtype associates with immunological changes in the microenvironment (2017, methodology): “We knocked down NF1 using two different hairpins in TS603 human NF1 wild-type glioma cells (Figures 4F and 4G) (Rohle et al., 2013), andmeasured the recruitment of both human cultured microglial cells and freshly isolated GBM-associated macrophages using a transwell assay (Figures 4H–4K).”
Cholangiocarcinoma — evolving concepts and therapeutic strategies (2017, neutral): “Smallmolecule inhibitors of mutant IDH1 or IDH2 have shown favourable efficacy in preclinical studies 123,124 ; consequently, orally bio available inhibitors have entered clinical trials.”
Targeting Metabolism for Cancer Therapy (2017, background): “These epigenetic changes caused by D-2HG contribute to cancer phenotypes (Losman et al., 2013; Rohle et al., 2013; Saha et al., 2014; Wang et al., 2013), and have been proposed to promote oncogenesis by preventing normal cellular differentiation (Losman and Kaelin, 2013).”
Mutational Analysis Reveals the Origin and Therapy-driven Evolution of Recurrent Glioma (2013, neutral): “the current interest in IDH1 as a therapeutic target (16).”
Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “The IDH1 inhibitor (AGI-5198) impairs the growth and promotes the differentiation of glioma cells with the IDH1 mutation by inducing the demethylation of histone H3K9me3 and the expression of genes critical for gliogenic differentiation (Rohle et al., 2013).”
Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas (2015, neutral): “None 108/190 (57) 30/58 (52) 64/98 (65) 13/34 (38)”
Glioblastoma: pathology, molecular mechanisms and markers (2015, background): “1 3 specific for mutant IDH1/2 appears to be a practical lead for molecularly driven therapies and show promising preclinical results, either as a small molecular inhibitor or as a vaccine approach targeting the R132H protein as a tumorspecific neoantigen [135, 144].”
The molecular taxonomy of primary prostate cancer (2015, background): “, 2009), and if they are sensitive to newly developed IDH1-targeted therapeutics (Rohle et al., 2013).”
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “Because IDH mutants block cell differentiation and promote tumor transformation, and inhibition of mutant IDH (IDHi) can reverse this effect, R-2HG (as the major metabolic product of IDH mutants) has been regarded as an oncometabolite (Figueroa et al., 2010; Lu et al., 2012; Rohle et al., 2013;Wang ”