A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer
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.
Authors
- Hervé Dombret (ORCID: https://orcid.org/0000-0002-5454-6768)
- Alexandre Théron (ORCID: https://orcid.org/0000-0001-8793-4903)
- Étienne Lengliné (ORCID: https://orcid.org/0000-0003-0965-6615)
- Marie-Émilie Dourthe (ORCID: https://orcid.org/0000-0002-8326-5973)
- Ivan Nemazanyy (ORCID: https://orcid.org/0000-0001-8080-839X)
- Mathieu Simonin (ORCID: https://orcid.org/0000-0002-0448-8811)
- Vahid Asnafi (ORCID: https://orcid.org/0000-0002-6255-5314)
- Philippe Rousselot (ORCID: https://orcid.org/0000-0003-3238-4494)
- Guillaume P. Andrieu (ORCID: https://orcid.org/0000-0003-0289-4952)
- Olivier Hermine (ORCID: https://orcid.org/0000-0003-2574-3874)
- Nicolas Boissel (ORCID: https://orcid.org/0000-0003-2091-7927)
- Ambroise Marçais (ORCID: https://orcid.org/0000-0002-6844-7920)
- Aurélie Cabannes‐Hamy (ORCID: https://orcid.org/0000-0002-6064-3783)
- Jérome Doss
- Grégoire Huré
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Sorbonne Université (FR)
- Institut Necker Enfants Malades (FR)
- Hôpital Armand-Trousseau (FR)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Robert-Debré (FR)
- Hôpital Saint-Louis (FR)
- Centre Hospitalier de Versailles (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-04
- DOI
- https://doi.org/10.1038/s41467-025-57225-7
- Citations
- 9
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 15.93
Funders
- Agence Nationale de la Recherche
- Institut National Du Cancer