A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer

Guillaume P. Andrieu (), Mathieu Simonin, Aurélie Cabannes-Hamy, Etienne Lengliné, Ambroise Marçais, Alexandre Théron, Grégoire Huré, Jérome Doss, Ivan Nemazanyy, Marie Émilie Dourthe, Nicolas Boissel, Hervé Dombret, Philippe Rousselot, Olivier Hermine and Vahid Asnafi ()
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Guillaume P. Andrieu: Université Paris Cité
Mathieu Simonin: Université Paris Cité
Aurélie Cabannes-Hamy: APHP
Etienne Lengliné: Université Paris Cité
Ambroise Marçais: Université Paris Cité
Alexandre Théron: Université de Montpellier
Grégoire Huré: Université Paris Cité
Jérome Doss: Université Paris Cité
Ivan Nemazanyy: Université Paris Cité
Marie Émilie Dourthe: Université Paris Cité
Nicolas Boissel: Université Paris Cité
Hervé Dombret: Université Paris Cité
Philippe Rousselot: APHP
Olivier Hermine: Université Paris Cité
Vahid Asnafi: Université Paris Cité

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57225-7

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DOI: 10.1038/s41467-025-57225-7

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