A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer PMID: 40038309

ADC Targets in Oncology

2026-04-10

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

1. Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Necker Enfants-Malades, Université Paris Cité, Paris, France. [email protected].
2. Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR8253, Université Paris Cité, Paris, France. [email protected].
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. [email protected].
14. Institut Necker-Enfants Malades (INEM), INSERM U1151 CNRS UMR8253, Université Paris Cité, Paris, France. [email protected].

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.