Genomic alterations and their correlation with metabolic-related genes in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Non-small cell lung cancer (NSCLC) has poor survival rates due to therapeutic resistance and metastasis.
• Genomic alterations like KRAS, EGFR, TP53, and MYC drive metabolic reprogramming, fueling tumor growth and resistance.
• Understanding these genotype-metabolism links is crucial for novel therapeutic strategies.

Purpose of the Study:

• To review and synthesize evidence linking specific genomic alterations in NSCLC to distinct metabolic phenotypes.
• To examine the immunometabolic impact of co-occurring mutations.
• To identify mutation-specific metabolic vulnerabilities and therapeutic targets.

Main Methods:

• Literature synthesis integrating genomic, metabolic, and immunologic profiling data.
• Analysis of variant-specific KRAS alleles (G12C, G12D, G12V) and TP53 mutations.
• Examination of co-occurring mutations (e.g., KRAS with TP53 or STK11/LKB1).

Main Results:

• Distinct metabolic dependencies arise from genomic alterations: KRAS-driven tumors show enhanced glycolysis/glutaminolysis, EGFR-mutant tumors increased lipogenesis, and TP53 loss promotes metabolic flexibility.
• Tumor microenvironment alterations (lactate accumulation, glucose depletion) impair CD8+ T-cell function, aiding immune evasion.
• Combination therapies pairing genomic-targeted agents with metabolic inhibitors show promise against adaptive resistance.

Conclusions:

• Genomic profiling in NSCLC reveals mutation-specific metabolic vulnerabilities.
• Targeting metabolic pathways in conjunction with genomic alterations offers a promising avenue for precision oncology.
• Integrating genomic and metabolic data may improve NSCLC treatment strategies and patient outcomes.