title: PIK3CAmutant tumors depend on oxoglutarate dehydrogenase.
abstract: OncogenicPIK3CAmutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale loss-of-function screening in a large number of genomically annotated cancer cell lines. As expected, we found thatPIK3CAmutant cancer cells requirePIK3CAbut also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustainPIK3CAmutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy withinPIK3CAmutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD+regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, becausePIK3CAmutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD+/NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Nina
authors.initials: N
authors.lastname: Ilic
authors.affiliation: Laboratory of Metabolic Regulation and Genetics, The Rockefeller University, New York, NY 10065.
authors.forename: Kıvanç
authors.initials: K
authors.lastname: Birsoy
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Aguirre
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.|Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Nora
authors.initials: N
authors.lastname: Kory
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.|Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Pacold
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Shambhavi
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Moody
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: DeAngelo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Spardy
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Freinkman
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Aviad
authors.identifier: 0000-0002-3797-1877
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Glenn S
authors.initials: GS
authors.lastname: Cowley
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.affiliation: Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
authors.forename: Hans R
authors.initials: HR
authors.lastname: Widlund
authors.affiliation: Broad Institute of MIT and Harvard University, Cambridge, MA 02142.|Whitehead Institute for Biomedical Research, Cambridge, MA 02142.|David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215; william_hahn@dfci.harvard.edu.|Broad Institute of MIT and Harvard University, Cambridge, MA 02142.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002952:Citric Acid Cycle / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: D009363:Neoplasm Proteins; D007655:Ketoglutarate Dehydrogenase Complex; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: 2OG; OGDH; PIK3CA; TCA cycle; glycolysis