title: IDH1 mutations alter citric acid cycle metabolism and increase dependence on oxidative mitochondrial metabolism.
abstract: Oncogenic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in several types of cancer, but the metabolic consequences of these genetic changes are not fully understood. In this study, we performed (13)C metabolic flux analysis on a panel of isogenic cell lines containing heterozygous IDH1/2 mutations. We observed that under hypoxic conditions, IDH1-mutant cells exhibited increased oxidative tricarboxylic acid metabolism along with decreased reductive glutamine metabolism, but not IDH2-mutant cells. However, selective inhibition of mutant IDH1 enzyme function could not reverse the defect in reductive carboxylation activity. Furthermore, this metabolic reprogramming increased the sensitivity of IDH1-mutant cells to hypoxia or electron transport chain inhibition in vitro. Lastly, IDH1-mutant cells also grew poorly as subcutaneous xenografts within a hypoxic in vivo microenvironment. Together, our results suggest therapeutic opportunities to exploit the metabolic vulnerabilities specific to IDH1 mutation.
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Alexandra R
authors.initials: AR
authors.lastname: Grassian
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Parker
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Ajit S
authors.initials: AS
authors.lastname: Divakaruni
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Courtney R
authors.initials: CR
authors.lastname: Green
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Xiamei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Slocum
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Minying
authors.initials: M
authors.lastname: Pu
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Fallon
authors.initials: F
authors.lastname: Lin
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Chad
authors.initials: C
authors.lastname: Vickers
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Carol
authors.initials: C
authors.lastname: Joud-Caldwell
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Franklin
authors.initials: F
authors.lastname: Chung
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Erika D
authors.initials: ED
authors.lastname: Handly
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Christopher
authors.initials: C
authors.lastname: Straub
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Growney
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, CaliforniaAuthors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Anne N
authors.initials: AN
authors.lastname: Murphy
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California cmetallo@ucsd.edu raymond.pagliarini@novartis.com.
authors.forename: Raymond
authors.initials: R
authors.lastname: Pagliarini
authors.affiliation: Authors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, CaliforniaAuthors' Affiliations: Novartis Institutes for Biomedical Research; Koch Institute for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Departments of Bioengineering and Pharmacology; and Moores Cancer Center, University of California, San Diego, La Jolla, California cmetallo@ucsd.edu raymond.pagliarini@novartis.com.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015687:Cell Hypoxia; D002952:Citric Acid Cycle; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005973:Glutamine / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D013312:Stress, Physiological; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005973:Glutamine; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
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