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<p>Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, with 5-year survival rates below 21% primarily due to therapeutic resistance and metastatic progression. Genomic alterations in KRAS, EGFR, TP53, and MYC drive metabolic reprogramming that sustains tumor proliferation and therapy resistance. This review synthesizes evidence linking specific genomic alterations, including variant-specific KRAS alleles (G12C, G12D, and G12V) and TP53 gain- or loss-of-function mutations, to distinct metabolic phenotypes in NSCLC. It further examines the immunometabolic consequences of co-occurring mutations such as KRAS with TP53 or STK11/LKB1. The literature synthesis integrates genomic, metabolic, and immunologic profiling data to identify mutation-specific metabolic vulnerabilities and therapeutic targets. Genomic alterations establish distinct metabolic dependencies: KRAS-driven tumors exhibit enhanced glycolysis and glutaminolysis, EGFR-mutant tumors demonstrate increased lipogenesis, and TP53 loss promotes metabolic flexibility. Accumulation of lactate and depletion of glucose in the tumor microenvironment suppress CD8+ T-cell function, facilitating immune evasion. Rational combination strategies that pair genomic-targeted agents (sotorasib and adagrasib) with metabolic inhibitors (CB-839 and TVB-2640) show promise in overcoming adaptive resistance. Integrating genomic and metabolic profiling may enhance precision oncology approaches and improve clinical outcomes.</p> Graphical Abstract <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年2月11日

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  • Gauri Gaur,
  • Niraj Kumar Jha,
  • Lokesh Gambhir,
  • Seema V. Acharya,
  • Dhruv Kumar

摘要

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality worldwide, with 5-year survival rates below 21% primarily due to therapeutic resistance and metastatic progression. Genomic alterations in KRAS, EGFR, TP53, and MYC drive metabolic reprogramming that sustains tumor proliferation and therapy resistance. This review synthesizes evidence linking specific genomic alterations, including variant-specific KRAS alleles (G12C, G12D, and G12V) and TP53 gain- or loss-of-function mutations, to distinct metabolic phenotypes in NSCLC. It further examines the immunometabolic consequences of co-occurring mutations such as KRAS with TP53 or STK11/LKB1. The literature synthesis integrates genomic, metabolic, and immunologic profiling data to identify mutation-specific metabolic vulnerabilities and therapeutic targets. Genomic alterations establish distinct metabolic dependencies: KRAS-driven tumors exhibit enhanced glycolysis and glutaminolysis, EGFR-mutant tumors demonstrate increased lipogenesis, and TP53 loss promotes metabolic flexibility. Accumulation of lactate and depletion of glucose in the tumor microenvironment suppress CD8+ T-cell function, facilitating immune evasion. Rational combination strategies that pair genomic-targeted agents (sotorasib and adagrasib) with metabolic inhibitors (CB-839 and TVB-2640) show promise in overcoming adaptive resistance. Integrating genomic and metabolic profiling may enhance precision oncology approaches and improve clinical outcomes.

Graphical Abstract