A metabolic synthetic lethality of PI3K-driven cancer

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.