2. Academic Validation
  3. A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer

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

  • Nat Commun. 2025 Mar 4;16(1):2191. doi: 10.1038/s41467-025-57225-7.
Guillaume P Andrieu 1 2,  Mathieu Simonin 3 4 5,  Aurélie Cabannes-Hamy 6,  Etienne Lengliné 7,  Ambroise Marçais 3 8,  Alexandre Théron 9,  Grégoire Huré 3 4,  Jérome Doss 3 4,  Ivan Nemazanyy 10,  Marie Émilie Dourthe 3 4 11,  Nicolas Boissel 7,  Hervé Dombret 7,  Philippe Rousselot 6,  Olivier Hermine 8 12,  Vahid Asnafi 13 14
Affiliations

Affiliations

  • 1 Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker Enfants-Malades, Université Paris Cité, Paris, France. guillaume.andrieu@inserm.fr.
  • 2 Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR8253, Université Paris Cité, Paris, France. guillaume.andrieu@inserm.fr.
  • 3 Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker Enfants-Malades, Université Paris Cité, Paris, France.
  • 4 Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR8253, Université Paris Cité, Paris, France.
  • 5 Department of Pediatric Hematology and Oncology, AP-HP, Hôpital Armand Trousseau, Université Paris Sorbonne, Paris, France.
  • 6 Service d'Hématologie et d'Oncologie, Hôpital Universitaire de Versailles, APHP, Versailles, France.
  • 7 Laboratory of Hematology and Institut de Recherche Saint-Louis EA3518, Hôpital Universitaire Saint-Louis, Université Paris Cité, Paris, France.
  • 8 Service d'Hématologie Adulte, Hôpital Universitaire Necker-Enfants Malades, APHP, Université Paris Cité, Paris, France.
  • 9 Department of Pediatric Oncology and Hematology, Hôpital Universitaire de Montpellier, Université de Montpellier, Montpellier, France.
  • 10 Platform for Metabolic Analyses, Structure Fédérative de Recherche Necker, INSERM US24, CNRS UAR3633, Université Paris Cité, Paris, France.
  • 11 Department of Pediatric Hematology and Immunology, AP-HP, Hôpital Universitaire Robert Debré, Université Paris Cité, Paris, France.
  • 12 Department of Hematology, INSERM U1163, IMAGINE Institute, Hôpital Universitaire Necker Enfants-Malades, Université Paris Cité, Paris, France.
  • 13 Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker Enfants-Malades, Université Paris Cité, Paris, France. vahid.asnafi@aphp.fr.
  • 14 Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR8253, Université Paris Cité, Paris, France. vahid.asnafi@aphp.fr.
PMID: 40038309 DOI: 10.1038/s41467-025-57225-7
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.

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