Fiche publication
Date publication
mars 2025
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr MARCAIS Ambroise
Tous les auteurs :
Andrieu GP, Simonin M, Cabannes-Hamy A, Lengliné E, Marçais A, Théron A, Huré G, Doss J, Nemazanyy I, Dourthe MÉ, Boissel N, Dombret H, Rousselot P, Hermine O, Asnafi V
Lien Pubmed
Résumé
The deregulated activation of the phosphoinositide 3-kinase (PI3K) pathway is a hallmark of aggressive tumors with metabolic plasticity, eliciting their adaptation to the microenvironment and resistance to chemotherapy. A significant gap lies between the biological features of PI3K-driven tumors and the specific targeting of their vulnerabilities. Here, we explore the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We report a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR reveals the singular plasticity of PI3K-altered cells toward the mobilization of glutamine as a salvage pathway to ensure their survival. Subsequently, the combination of glutamine degradation and mTOR inhibition demonstrates robust cytotoxicity in PI3K-driven solid and hematological tumors in pre-clinical and clinical settings. We propose a novel therapeutic strategy to circumvent metabolic adaptation and efficiently target PI3K-driven cancer.
Mots clés
Humans, Animals, TOR Serine-Threonine Kinases, metabolism, Cell Line, Tumor, Phosphatidylinositol 3-Kinases, metabolism, Glutamine, metabolism, Glycolysis, drug effects, Signal Transduction, drug effects, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, metabolism, MTOR Inhibitors, pharmacology, Female, Xenograft Model Antitumor Assays
Référence
Nat Commun. 2025 03 4;16(1):2191
