title: Small molecule activation of PKM2 in cancer cells induces serine auxotrophy.
abstract: Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM2 isoform, effectively constraining lower glycolysis. Here, we report the discovery of PKM2 activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM2 activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the nonessential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM2 activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM2 expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress.
authors.affiliation: Agios Pharmaceuticals, 38 Sidney Street, Cambridge, MA 02139, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kung
authors.forename: Jeff
authors.initials: J
authors.lastname: Hixon
authors.forename: Sung
authors.initials: S
authors.lastname: Choe
authors.forename: Kevin
authors.initials: K
authors.lastname: Marks
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.forename: Erin
authors.initials: E
authors.lastname: Murphy
authors.forename: Byron
authors.initials: B
authors.lastname: DeLaBarre
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cianchetta
authors.forename: Shalini
authors.initials: S
authors.lastname: Sethumadhavan
authors.forename: Xiling
authors.initials: X
authors.lastname: Wang
authors.forename: Shunqi
authors.initials: S
authors.lastname: Yan
authors.forename: Yi
authors.initials: Y
authors.lastname: Gao
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.forename: Wentao
authors.initials: W
authors.lastname: Wei
authors.forename: Fan
authors.initials: F
authors.lastname: Jiang
authors.forename: Shaohui
authors.initials: S
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Qian
authors.forename: Jeff
authors.initials: J
authors.lastname: Saunders
authors.forename: Ed
authors.initials: E
authors.lastname: Driggers
authors.forename: Hin Koon
authors.initials: HK
authors.lastname: Woo
authors.forename: Kaiko
authors.initials: K
authors.lastname: Kunii
authors.forename: Stuart
authors.initials: S
authors.lastname: Murray
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.forename: Katharine
authors.initials: K
authors.lastname: Yen
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.forename: Francesco G
authors.initials: FG
authors.lastname: Salituro
authors.forename: Lenny
authors.initials: L
authors.lastname: Dang
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D012694:Serine / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D012694:Serine; D054852:Small Molecule Libraries; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins