PHGDH is a targetable driver of PDAC progression

Area of Science:

• Oncology
• Metabolic Pathways
• Cancer Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) develops in a nutrient-poor microenvironment.
• The role of de novo serine synthesis in PDAC progression is not well understood.
• Phosphoglycerate dehydrogenase (PHGDH) is key to serine biosynthesis.

Purpose of the Study:

• To investigate the stage-specific role of de novo serine synthesis in PDAC.
• To explore the function of PHGDH in PDAC development and metabolism.
• To identify potential therapeutic vulnerabilities in PDAC related to serine metabolism.

Main Methods:

• Analysis of PHGDH expression in human and mouse PDAC specimens.
• Genetically engineered mouse models with inducible PHGDH knockdown.
• Stable isotope tracing and metabolomic profiling.
• Assessment of tumor response to glutamine antagonist DRP-104.

Main Results:

• PHGDH expression increases progressively during PDAC development.
• PHGDH loss delays PDAC progression and does not increase reliance on exogenous serine.
• PHGDH deficiency suppresses mTOR signaling and impairs glutamine metabolism.
• PHGDH-deficient tumors show selective sensitivity to the glutamine antagonist DRP-104.

Conclusions:

• PHGDH supports PDAC progression via glutamine metabolism and mTOR signaling, not primarily serine provision.
• PHGDH deficiency creates a synthetic lethal vulnerability to glutamine antagonism.
• Combining serine synthesis inhibitors with glutamine-targeting therapies is a potential strategy for PDAC treatment.