title: Extreme Vulnerability of IDH1 Mutant Cancers to NAD+ Depletion.
abstract: Heterozygous mutation of IDH1 in cancers modifies IDH1 enzymatic activity, reprogramming metabolite flux and markedly elevating 2-hydroxyglutarate (2-HG). Here, we found that 2-HG depletion did not inhibit growth of several IDH1 mutant solid cancer types. To identify other metabolic therapeutic targets, we systematically profiled metabolites in endogenous IDH1 mutant cancer cells after mutant IDH1 inhibition and discovered a profound vulnerability to depletion of the coenzyme NAD+. Mutant IDH1 lowered NAD+ levels by downregulating the NAD+ salvage pathway enzyme nicotinate phosphoribosyltransferase (Naprt1), sensitizing to NAD+ depletion via concomitant nicotinamide phosphoribosyltransferase (NAMPT) inhibition. NAD+ depletion activated the intracellular energy sensor AMPK, triggered autophagy, and resulted in cytotoxicity. Thus, we identify NAD+ depletion as a metabolic susceptibility of IDH1 mutant cancers.
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Tateishi
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Shota
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Franziska
authors.initials: F
authors.lastname: Loebel
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Nina
authors.initials: N
authors.lastname: Lelic
authors.affiliation: Sanofi Oncology, Cambridge, MA 02139, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Wiederschain
authors.affiliation: Sanofi Oncology, Cambridge, MA 02139, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Bedel
authors.affiliation: Sanofi Oncology, Cambridge, MA 02139, USA.
authors.forename: Gejing
authors.initials: G
authors.lastname: Deng
authors.affiliation: Sanofi Oncology, Cambridge, MA 02139, USA.
authors.forename: Bailin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Sanofi Oncology, Cambridge, MA 02139, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: He
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Xu
authors.initials: X
authors.lastname: Shi
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Jing-Ruey J
authors.initials: JJ
authors.lastname: Yeh
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Curry
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Sudhandra
authors.initials: S
authors.lastname: Sundaram
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Fares
authors.initials: F
authors.lastname: Nigim
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Mara V A
authors.initials: MVA
authors.lastname: Koerner
authors.affiliation: Department of Pathology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Ho
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Fisher
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Roider
authors.affiliation: Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Lajos V
authors.initials: LV
authors.lastname: Kemeny
authors.affiliation: Weizmann Institute of Science, Rehovot 7610001, Israel.
authors.forename: Yardena
authors.initials: Y
authors.lastname: Samuels
authors.affiliation: Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Batchelor
authors.affiliation: Divisions of Neuro-Oncology and Hematology/Oncology, Department of Neurology, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: chia01@nyumc.org.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, Translational Neuro-Oncology Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: cahill@mgh.harvard.edu.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cahill
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D005977:Glutarates / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D055432:Metabolomics / Q000379:methods; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009154:Mutation; D009243:NAD / Q000172:deficiency*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010430:Pentosyltransferases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D005977:Glutarates; D009243:NAD; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D010430:Pentosyltransferases; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D055372:AMP-Activated Protein Kinases; C021864:nicotinate phosphoribosyltransferase