A metabolic synthetic lethality of phosphoinositide 3-kinase-driven cancer

Area of Science:

• Oncology
• Cancer Metabolism
• Molecular Biology

Background:

• Deregulation of the phosphoinositide 3-kinase (PI3K) pathway is common in aggressive cancers, conferring metabolic plasticity and therapeutic resistance.
• PI3K-driven tumors, particularly T-cell acute lymphoblastic leukemia (T-ALL), possess unique metabolic vulnerabilities that remain inadequately targeted.
• Understanding the metabolic adaptations in PI3K-altered cancers is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the metabolic liabilities associated with PI3K signaling alterations in T-ALL.
• To identify and exploit the metabolic crosstalk between glutaminolysis and glycolysis in PI3K-driven cancers.
• To develop a novel therapeutic strategy targeting metabolic vulnerabilities in PI3K-altered malignancies.

Main Methods:

• Exploration of metabolic pathways in PI3K-altered T-ALL models.
• Pharmaceutical inhibition of the mechanistic target of rapamycin (mTOR) pathway.
• Assessment of combined glutamine degradation and mTOR inhibition in pre-clinical and clinical cancer models.

Main Results:

• A metabolic crosstalk linking glutaminolysis and glycolysis, driven by PI3K signaling, was identified.
• PI3K-altered cells exhibit plasticity, utilizing glutamine as a salvage pathway upon mTOR inhibition.
• The combination of glutamine degradation inhibition and mTOR inhibition demonstrated significant cytotoxicity against PI3K-driven solid and hematological tumors.

Conclusions:

• Targeting the metabolic crosstalk between glutaminolysis and glycolysis is a viable strategy for PI3K-driven cancers.
• Combined inhibition of glutamine metabolism and mTOR effectively overcomes cancer cell adaptive resistance.
• This study proposes a novel therapeutic approach to circumvent metabolic adaptation and target PI3K-driven cancers.