title: High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells.
abstract: Alterations in metabolic activities are cancer hallmarks that offer a wide range of new therapeutic opportunities. Here we decipher the interplay between mTORC1 activity and glucose metabolism in acute myeloid leukemia (AML). We show that mTORC1 signaling that is constantly overactivated in AML cells promotes glycolysis and leads to glucose addiction. The level of mTORC1 activity determines the sensitivity of AML cells to glycolysis inhibition as switch-off mTORC1 activity leads to glucose-independent cell survival that is sustained by an increase in mitochondrial oxidative phosphorylation. Metabolic analysis identified the pentose phosphate pathway (PPP) as an important pro-survival pathway for glucose metabolism in AML cells with high mTORC1 activity and provided a clear rational for targeting glucose-6-phosphate dehydrogenase (G6PD) in AML. Indeed, our analysis of the cancer genome atlas AML database pinpointed G6PD as a new biomarker in AML, as its overexpression correlated with an adverse prognosis in this cohort. Targeting the PPP using the G6PD inhibitor 6-aminonicotinamide induces in vitro and in vivo cytotoxicity against AML cells and synergistically sensitizes leukemic cells to chemotherapy. Our results demonstrate that high mTORC1 activity creates a specific vulnerability to G6PD inhibition that may work as a new AML therapy.
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Poulain
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Sujobert
authors.affiliation: INSERM UMR1163, Laboratory of Cellular and Molecular Mechanisms of Haematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Zylbersztejn
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Barreau
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: L
authors.initials: L
authors.lastname: Stuani
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Lambert
authors.affiliation: Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.|LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France.
authors.forename: T L
authors.initials: TL
authors.lastname: Palama
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Chesnais
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Birsen
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: F
authors.initials: F
authors.lastname: Vergez
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: T
authors.initials: T
authors.lastname: Farge
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service de Diagnostic Biologique Automatisé, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Chenevier-Gobeaux
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Fraisse
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.
authors.forename: F
authors.initials: F
authors.lastname: Bouillaud
authors.affiliation: CNRS UMR7292, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Debeissat
authors.affiliation: CNRS UMR7292, Tours, France.
authors.forename: O
authors.initials: O
authors.lastname: Herault
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Récher
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Lacombe
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie biologique, F-75014 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Fontenay
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Mayeux
authors.affiliation: INSERM UMR1163, Laboratory of Cellular and Molecular Mechanisms of Haematological Disorders and Therapeutic Implications, Paris, France.|Paris Descartes-Sorbonne Paris Cité University, Imagine Institute, Paris, France.
authors.forename: T T
authors.initials: TT
authors.lastname: Maciel
authors.affiliation: Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.|LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France.
authors.forename: J-C
authors.initials: JC
authors.lastname: Portais
authors.affiliation: INSERM, UMR1037, Cancer Research Center of Toulouse, Toulouse, France.|Université de Toulouse III Paul Sabatier, INSA, UPS, INP, LISBP, Toulouse, France.
authors.forename: J-E
authors.initials: JE
authors.lastname: Sarry
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie clinique, F-75014 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Tamburini
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie clinique, F-75014 Paris, France.
authors.forename: D
authors.initials: D
authors.lastname: Bouscary
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|CNRS UMR8104, Paris, France.|Faculté de Médecine Sorbonne Paris Cité, Université Paris Descartes, Paris, France.|Equipe Labellisée Ligue Nationale Contre le Cancer (LNCC), Paris, France.|Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Service d'Hématologie clinique, F-75014 Paris, France.
authors.forename: N
authors.initials: N
authors.lastname: Chapuis
mesh_terms: D005947:Glucose / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000037:antagonists & inhibitors*; D006019:Glycolysis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D010085:Oxidative Phosphorylation
chemical_list: D005954:Glucosephosphate Dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D005947:Glucose