Metabolism-Based Molecular Subtyping Endows Effective Ketogenic Therapy in p53-Mutant Colon Cancer

Area of Science:

• Oncology
• Cancer Metabolism
• Metabolic Therapies

Background:

• Targeting cancer metabolism is a key therapeutic strategy.
• Accurate molecular and metabolic subtyping is crucial for clinical success in cancer therapy.
• Ketogenic interventions show promise but require precise patient stratification.

Purpose of the Study:

• To identify distinct molecular and metabolic subtypes of colon cancer relevant to ketogenic treatment.
• To investigate the mechanisms underlying differential responses to ketogenic therapy.
• To explore novel therapeutic targets for overcoming resistance to ketogenic interventions.

Main Methods:

• Metabolic subtyping of colon cancer based on glycolysis and ketolysis.
• Analysis of metabolic enzyme profiles and mitochondrial function.
• In vitro and in vivo assessment of responses to ketone-containing interventions.
• Investigation of p53 mutation status and its role in metabolic reprogramming.

Main Results:

• Two subtypes identified: glycolytic (glycolysis+/ketolysis-) and ketolytic (glycolysis+/ketolysis+).
• Subtypes exhibit distinct metabolic enzyme profiles and mitochondrial dysfunction.
• p53-mutated tumors can switch to a ketolytic subtype under glucose limitation, developing resistance to ketogenic therapy.
• Upregulation of ketolytic enzymes like OXCT1 by mutant p53 contributes to resistance.
• An allosteric activator of mutant p53 suppressed tumor growth by blocking metabolic reprogramming.

Conclusions:

• Metabolic subtyping is essential for guiding ketogenic therapy in colon cancer.
• Mutant p53 plays a critical role in mediating resistance to ketogenic treatment.
• Targeting mutant p53 represents a potential synthetic lethality strategy in combination with ketogenic therapy.