Methionine Restriction Reduces Lung Cancer Progression and Increases Chemotherapy Response

Area of Science:

• Oncology
• Metabolic pathways in cancer
• Dietary interventions and cancer therapy

Background:

• Aggressive cancers, including non-small cell lung cancer (NSCLC), have high mortality rates.
• Targeting tumor metabolism via dietary interventions is a promising strategy to improve cancer treatment outcomes.
• KRAS/Lkb1-mutant NSCLC is an aggressive subtype with limited therapeutic options.

Purpose of the Study:

• To investigate the impact of methionine restriction (MR) on KRAS/Lkb1-mutant NSCLC progression and carboplatin treatment efficacy.
• To elucidate the underlying mechanisms, including effects on tumor lineage, immune microenvironment, and cystathionine-β-synthase (CBS) expression.
• To assess the potential of MR as an adjunct therapy for NSCLC.

Main Methods:

• Utilized an autochthonous KRAS/Lkb1-mutant NSCLC mouse model.
• Administered methionine restriction (MR) as a dietary intervention.
• Assessed tumor progression, carboplatin treatment efficacy, tumor immune microenvironment (TIME), cell cycle arrest, apoptosis, and T cell proliferation.
• Analyzed cystathionine-β-synthase (CBS) expression in human NSCLC cell lines and patient tumors.

Main Results:

• Methionine restriction significantly decreased tumor progression and increased carboplatin efficacy in the NSCLC mouse model.
• MR prevented lineage switching and reduced tumor-infiltrating neutrophils, altering the TIME.
• LKB1 mutations are linked to altered CBS expression and carboplatin resistance, which can be partially rescued by MR.
• CBS expression is correlated with smoking and specific NSCLC subtypes, suggesting a role in oxidative stress and lineage fate.

Conclusions:

• Methionine restriction is a viable dietary intervention to slow tumor growth in aggressive NSCLC.
• MR enhances the efficacy of carboplatin chemotherapy and modulates the tumor immune microenvironment.
• Targeting methionine metabolism and CBS expression presents a novel therapeutic avenue for NSCLC.