title: Differential Aspartate Usage Identifies a Subset of Cancer Cells Particularly Dependent on OGDH.
abstract: Although aberrant metabolism in tumors has been well described, the identification of cancer subsets with particular metabolic vulnerabilities has remained challenging. Here, we conducted an siRNA screen focusing on enzymes involved in the tricarboxylic acid (TCA) cycle and uncovered a striking range of cancer cell dependencies on OGDH, the E1 subunit of the alpha-ketoglutarate dehydrogenase complex. Using an integrative metabolomics approach, we identified differential aspartate utilization, via the malate-aspartate shuttle, as a predictor of whether OGDH is required for proliferation in 3D culture assays and for the growth of xenograft tumors. These findings highlight an anaplerotic role of aspartate and, more broadly, suggest that differential nutrient utilization patterns can identify subsets of cancers with distinct metabolic dependencies for potential pharmacological intervention.
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Allen
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Danielle B
authors.initials: DB
authors.lastname: Ulanet
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Pirman
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mahoney
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: John
authors.initials: J
authors.lastname: Coco
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Yaguang
authors.initials: Y
authors.lastname: Si
authors.affiliation: Shanghai ChemPartner Co. Ltd., 998 Halei Road, Pudong, 201203 Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai ChemPartner Co. Ltd., 998 Halei Road, Pudong, 201203 Shanghai, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Huang
authors.affiliation: Shanghai ChemPartner Co. Ltd., 998 Halei Road, Pudong, 201203 Shanghai, China.
authors.forename: Jinmin
authors.initials: J
authors.lastname: Ren
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Michelle F
authors.initials: MF
authors.lastname: Clasquin
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: Artin
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Zi Peng
authors.initials: ZP
authors.lastname: Fan
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Murtie
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.affiliation: Agios Pharmaceuticals, 88 Sidney Street, Cambridge, MA 02139, USA. Electronic address: gromoslaw.smolen@agios.com.
authors.forename: Gromoslaw A
authors.initials: GA
authors.lastname: Smolen
mesh_terms: D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002952:Citric Acid Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D001224:Aspartic Acid; D007655:Ketoglutarate Dehydrogenase Complex
keywords: Krebs cycle; OGDH; TCA cycle; alpha-ketoglutarate dehydrogenase; aspartate; cancer metabolism; citric acid cycle; malate-aspartate shuttle; oxoglutarate dehydrogenase; target validation