title: An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
abstract: 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Rohle
authors.forename: Janeta
authors.initials: J
authors.lastname: Popovici-Muller
authors.forename: Nicolaos
authors.initials: N
authors.lastname: Palaskas
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.forename: Christian
authors.initials: C
authors.lastname: Grommes
authors.forename: Carl
authors.initials: C
authors.lastname: Campos
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsoi
authors.forename: Owen
authors.initials: O
authors.lastname: Clark
authors.forename: Barbara
authors.initials: B
authors.lastname: Oldrini
authors.forename: Evangelia
authors.initials: E
authors.lastname: Komisopoulou
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.forename: Alicia
authors.initials: A
authors.lastname: Pedraza
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schalm
authors.forename: Lee
authors.initials: L
authors.lastname: Silverman
authors.forename: Alexandra
authors.initials: A
authors.lastname: Miller
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.forename: Andrew
authors.initials: A
authors.lastname: Kernytsky
authors.forename: Marc K
authors.initials: MK
authors.lastname: Rosenblum
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Biller
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Yen
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
mesh_terms: D000818:Animals; D044482:Benzeneacetamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D005977:Glutarates / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D051379:Mice; D016513:Mice, SCID; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D034622:RNA Interference; D023041:Xenograft Model Antitumor Assays
chemical_list: C581156:AGI-5198; D044482:Benzeneacetamides; D004791:Enzyme Inhibitors; D005977:Glutarates; D006657:Histones; D007093:Imidazoles; D050505:Mutant Proteins; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
references.citation: Oncologist. 2012;17(1):72-9
references.pmid: 22180306
references.citation: Nature. 2007 Jan 11;445(7124):168-76
references.pmid: 17151600
references.citation: Science. 2008 Sep 26;321(5897):1807-12
references.pmid: 18772396
references.citation: J Neurosci. 2008 Jan 2;28(1):264-78
references.pmid: 18171944
references.citation: Am J Pathol. 2009 Apr;174(4):1149-53
references.pmid: 19246647
references.citation: ACS Med Chem Lett. 2012 Sep 17;3(10):850-5
references.pmid: 24900389
references.citation: J Clin Oncol. 2010 Aug 1;28(22):3636-43
references.pmid: 20567020
references.citation: N Engl J Med. 2009 Feb 19;360(8):765-73
references.pmid: 19228619
references.citation: Nature. 2012 Feb 15;483(7390):474-8
references.pmid: 22343901
references.citation: J Pathol. 2011 Jul;224(3):334-43
references.pmid: 21598255
references.citation: Acta Neuropathol. 2007 Aug;114(2):97-109
references.pmid: 17618441
references.citation: EMBO Rep. 2011 May;12(5):463-9
references.pmid: 21460794
references.citation: Nature. 2012 Feb 15;483(7390):484-8
references.pmid: 22343896
references.citation: Cancer Cell. 2002 Apr;1(3):269-77
references.pmid: 12086863
references.citation: Nature. 2010 Jun 17;465(7300):966
references.pmid: 20559394
references.citation: Cancer Cell. 2010 Dec 14;18(6):553-67
references.pmid: 21130701
references.citation: Genes Dev. 2010 Jan 15;24(2):206-18
references.pmid: 20080956
references.citation: Curr Opin Struct Biol. 2010 Dec;20(6):659-72
references.pmid: 20888218
references.citation: Nature. 2012 Feb 15;483(7390):479-83
references.pmid: 22343889
references.citation: Nat Neurosci. 2010 Nov;13(11):1338-44
references.pmid: 20975758
references.citation: Nature. 2012 Aug 30;488(7413):656-9
references.pmid: 22763442
references.citation: Cancer Cell. 2011 Jan 18;19(1):17-30
references.pmid: 21251613
references.citation: Genes Dev. 2012 Sep 15;26(18):2038-49
references.pmid: 22925884
references.citation: N Engl J Med. 2009 Sep 10;361(11):1058-66
references.pmid: 19657110
references.citation: J Clin Oncol. 2011 Dec 1;29(34):4482-90
references.pmid: 22025148