Targeting one-carbon metabolism requires mTOR inhibition: a new therapeutic approach in osteosarcoma

Area of Science:

• Biochemistry
• Cancer Metabolism
• Oncology

Background:

• The enzyme 3-phosphoglycerate dehydrogenase (PHGDH) is crucial for serine biosynthesis and is often overexpressed in cancers, promoting tumor growth.
• PHGDH overexpression drives rapid cancer cell proliferation and survival.
• Understanding metabolic adaptations to PHGDH inhibition is key for developing targeted cancer therapies.

Purpose of the Study:

• To investigate the metabolic consequences of PHGDH inhibition in osteosarcoma.
• To elucidate the signaling pathways affected by PHGDH inhibition.
• To determine if PHGDH inhibition sensitizes osteosarcoma to mTOR inhibitors.

Main Methods:

• Osteosarcoma cell models were treated with PHGDH inhibitors.
• Metabolomic analysis was performed to identify accumulating metabolites.
• Western blotting and signaling pathway analysis were used to assess mTOR activation.

Main Results:

• PHGDH inhibition led to the accumulation of specific metabolites within osteosarcoma cells.
• The observed metabolite accumulation activated the mechanistic target of rapamycin (mTOR) signaling pathway.
• Osteosarcoma cells treated with PHGDH inhibitors showed increased sensitivity to non-rapalog mTOR inhibitors.

Conclusions:

• PHGDH inhibition triggers a metabolic rewiring in osteosarcoma.
• Metabolite accumulation upon PHGDH inhibition activates mTOR signaling.
• Targeting PHGDH can sensitize osteosarcoma to mTOR-directed therapies, representing a potential therapeutic vulnerability.