Nitrogen Trapping as a Therapeutic Strategy in Tumors with Mitochondrial Dysfunction

Area of Science:

• Biochemistry
• Cancer Biology
• Metabolic Pathways

Background:

• Cancer cells with mitochondrial dysfunction exhibit shared metabolic vulnerabilities.
• Targeting these metabolic phenotypes presents a potential therapeutic strategy.

Purpose of the Study:

• To investigate the efficacy of alpha-ketoglutarate (aKG) esters in targeting cancer cells with impaired oxidative phosphorylation (OXPHOS).
• To elucidate the underlying mechanism of aKG-induced cancer cell death.

Main Methods:

• Utilized OXPHOS-competent and incompetent cancer cell lines.
• Administered aKG esters and assessed cellular responses.
• Investigated aspartate levels, glutamic-oxaloacetic transaminase 1 (GOT1) activity, and mTOR signaling.
• Conducted preclinical mouse studies.

Main Results:

• aKG esters rapidly killed OXPHOS-deficient cancer cells by increasing intracellular aKG, sequestering nitrogen from aspartate via GOT1.
• Aspartate depletion led to adenylate depletion, mTOR inactivation, and glycolysis inhibition.
• Cytotoxicity was observed in various cancer types with compromised respiration (hypoxia or ETC inhibition).
• Preclinical studies showed aKG esters possess a good biosafety profile, selectively target OXPHOS-incompetent tumors, and inhibit growth and metastasis.

Conclusions:

• aKG esters induce cancer cell death by exploiting dependencies on aspartate synthesis in OXPHOS-deficient tumors.
• Cell-permeable aKG, alone or with ETC inhibitors, represents a promising anticancer strategy targeting metabolic vulnerabilities.