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: L Poulain, P Sujobert, F Zylbersztejn, S Barreau, L Stuani, M Lambert, T L Palama, V Chesnais, R Birsen, F Vergez, T Farge, C Chenevier-Gobeaux, M Fraisse, F Bouillaud, C Debeissat, O Herault, C Récher, C Lacombe, M Fontenay, P Mayeux, T T Maciel, J-C Portais, J-E Sarry, J Tamburini, D Bouscary, N Chapuis
• Journal: Leukemia (Leukemia) Vol. 31 Issue 11 Pg. 2326-2335 (11 2017) ISSN: 1476-5551 [Electronic] England
• PMID: 28280275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucosephosphate Dehydrogenase
• Mechanistic Target of Rapamycin Complex 1
• Glucose

Topics

• Glucose (metabolism)
• Glucosephosphate Dehydrogenase (antagonists & inhibitors)
• Glycolysis
• Humans
• Leukemia, Myeloid, Acute (enzymology, metabolism, pathology)
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Oxidative Phosphorylation