A metabolic synthetic lethality of PI3K-driven cancer

Author:

Asnafi Vahid1,Andrieu Guillaume1,Simonin Mathieu1,Cabannes-Hamy Aurélie2,Lengliné Etienne3,Marçais Ambroise4ORCID,Théron Alexandre5,Huré Grégoire6,Doss Jérome6,Dourthe Marie Emilie4,BOISSEL Nicolas7ORCID,Dombret Hervé8,Rousselot Philippe2,Hermine Olivier9

Affiliation:

1. Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades

2. Service d'Hématologie et d'Oncologie, CHU Versailles

3. Laboratory of Hematology and EA3518, University Hospital Saint-Louis, University of Paris

4. Service d'Hématologie Adulte, Hôpital Necker-Enfants Malades, APHP

5. Department of Pediatric Oncology and Hematology, University of Montpellier

6. Institut Necker Enfants-Malades

7. aphp hôpital saint louis paris

8. Hôpital Saint-Louis

9. CNRS UMR 8143, Université Paris Descartes

Abstract

Abstract The deregulated activation of the PI3 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 explored the metabolic liabilities of PI3K-altered T-cell acute lymphoblastic leukemia (T-ALL), an aggressive hematological cancer with dismal outcomes. We revealed a metabolic crosstalk linking glutaminolysis and glycolysis driven by PI3K signaling alterations. Pharmaceutical inhibition of mTOR revealed 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.

Publisher

Research Square Platform LLC

Reference57 articles.

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