title: Glioblastoma Therapy Can Be Augmented by Targeting IDH1-Mediated NADPH Biosynthesis.
abstract: NADPH is a critical reductant needed in cancer cells to fuel the biosynthesis of deoxynucleotides and antioxidants and to sustain stress-survival responses after radiation-induced DNA damage. Thus, one rational strategy to attack cancer cells is to target their heavy reliance on NADPH. Here, we report that the isocitrate dehydrogenase IDH1 is the most strongly upregulated NADPH-producing enzyme in glioblastoma (GBM). IDH1 silencing in GBM cells reduced levels of NADPH, deoxynucleotides, and glutathione and increased their sensitivity to radiation-induced senescence. Rescuing these metabolic restrictions was sufficient to reverse IDH1-mediated radiosensitization. In a murine xenograft model of human GBM, we found that IDH1 silencing significantly improved therapeutic responses to fractionated radiotherapy, when compared with either treatment alone. In summary, our work offers a mechanistic rationale for IDH1 inhibition as a metabolic strategy to improve the response of GBM to radiotherapy.Cancer Res; 77(4); 960-70. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. dwahl@med.umich.edu.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Wahl
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Joseph
authors.initials: J
authors.lastname: Dresser
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kari
authors.initials: K
authors.lastname: Wilder-Romans
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Parsels
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Shuang G
authors.initials: SG
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Mary
authors.initials: M
authors.lastname: Davis
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Maureen
authors.initials: M
authors.lastname: Kachman
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wernisch
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.affiliation: Department of Radiation Oncology, University of California San Francisco, San Francisco, CA.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Corey
authors.initials: C
authors.lastname: Speers
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.|Department of Molecular and Integrative Physiology; University of Michigan, Ann Arbor, Michigan.
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000532:radiotherapy*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000502:physiology*; D008297:Male; D051379:Mice; D009249:NADP / Q000096:biosynthesis*; D011836:Radiation Tolerance; D023041:Xenograft Model Antitumor Assays
chemical_list: D009249:NADP; D007521:Isocitrate Dehydrogenase; D000111:Acetylcysteine