The Emerging Roles of Metabolic Reprogramming in Non-Small Cell Lung Cancer Progression

Abstract

Lung cancer remains a leading cause of cancer-related mortality due to its capacity for silent metastasis and the significant challenges in achieving effective treatment. Currently, targeted therapies and chemotherapies are the primary options for advanced or inoperable lung cancer; however, their efficacy is often undermined by the cancer's ability to develop resistance through both genetic and non-genetic mechanisms. This review explores recent advances in understanding metabolic reprogramming in non-small cell lung cancer (NSCLC), focusing on its critical role in cancer progression. NSCLC cells exhibit heterogeneous activation of metabolic pathways influenced by their oncogenic mutations. Notably, their metabolic phenotypes evolve in response to environmental stressors and therapeutic pressures. Moreover, NSCLC cells engage in metabolic crosstalk with their microenvironment to enhance survival, leveraging distinct metabolic adaptations at both primary and metastatic sites. Despite extensive preclinical studies evaluating novel therapeutic strategies targeting these metabolic pathways, many have failed in clinical trials due to severe adverse effects. This is because the targeted pathways are crucial not only for cancer cells but also for normal cellular functions. Future research must prioritize approaches that selectively disrupt cancer-specific metabolic regulation to improve therapeutic outcomes.

Keywords: drug resistance; lung cancer; metabolic reprogramming; metastasis; stress tolerance.