Alanine catabolism as a targetable vulnerability for MYC-driven liver cancer

Area of Science:

• Oncology
• Metabolic pathways
• Cancer research

Background:

• Liver cancer is a major global health concern with limited effective treatments.
• MYC overexpression is linked to aggressive, difficult-to-treat liver tumors.
• MYC reprograms cancer cell metabolism, suggesting potential metabolic vulnerabilities.

Purpose of the Study:

• To investigate if MYC induces metabolic dependencies in liver cancer that can be targeted.
• To identify specific metabolic pathways crucial for MYC-driven liver tumor growth.
• To evaluate GPT2 as a potential therapeutic target in liver cancer.

Main Methods:

• Analysis of MYC-driven liver tumors for metabolic enzyme expression.
• Genetic ablation of GPT2 in mouse models of liver tumorigenesis.
• In vivo isotope tracing to study alanine metabolism.
• Treatment of mouse models with L-Cycloserine, a GPT2 inhibitor.

Main Results:

• MYC-driven liver cancers utilize alanine catabolism dependent on GPT2 for growth.
• GPT2 is the primary enzyme for alanine catabolism in these tumors.
• Inhibition of GPT2 significantly reduced liver tumor formation and growth.
• Alanine fuels pathways including the TCA cycle, nucleotide synthesis, and amino acid synthesis.

Conclusions:

• MYC-driven liver tumors exhibit a dependency on GPT2-mediated alanine metabolism.
• GPT2 is a targetable vulnerability in MYC-driven liver cancer.
• L-Cycloserine demonstrates potential as a therapeutic agent for this subset of liver cancer.