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.

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