Functional Genomics Reveals Synthetic Lethality between Phosphogluconate Dehydrogenase and Oxidative Phosphorylation.

Area of Science:

• Oncology
• Metabolic pathways
• Cancer cell biology

Background:

• Cancer cells adapt to therapies through regulatory circuit plasticity.
• Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is linked to fumarate hydratase (FH) deficiency and impaired oxidative phosphorylation (OXPHOS).

Purpose of the Study:

• To identify metabolic vulnerabilities synthetic lethal with OXPHOS deficiency in cancer.
• To explore phosphogluconate dehydrogenase (PGD) as a therapeutic target in FH-deficient cancers.

Main Methods:

• Conducted a genetic loss-of-function screen to identify synthetic lethal interactions.
• Utilized in vitro and in vivo models to assess the efficacy of PGD inhibition.
• Investigated the mechanistic effects of PGD inhibition on cellular metabolism and redox homeostasis.

Main Results:

• PGD inhibition significantly inhibited proliferation of FH-mutant cancer cells.
• PGD inhibition disrupted glycolysis, suppressed glutamine reductive carboxylation, and altered the NADP+/NADPH ratio.
• Combined inhibition of OXPHOS and PGD enhanced anti-cancer effects in OXPHOS-proficient contexts.

Conclusions:

• Phosphogluconate dehydrogenase (PGD) is a critical dependency in OXPHOS-deficient tumors.
• Targeting PGD represents a potential therapeutic strategy for HLRCC and other FH-deficient cancers.
• Metabolic vulnerabilities can be leveraged to overcome therapeutic resistance in cancer.