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Lung cancer is the most fatal malignancy worldwide, in part, due to high resistance to cytotoxic therapy. There is need for effective chemo-radio-sensitizers in lung cancer. In recent years, we began to understand the modulation of metabolism in cancer and its importance in tumor progression and survival after cytotoxic therapy. The activity of biosynthetic pathways, driven by the Growth Factor Receptor/Ras/PI3k/Akt/mTOR pathway, is balanced by the energy stress sensor pathway of LKB1/AMPK/p53. AMPK responds both to metabolic and genotoxic stress. Metformin, a well-tolerated anti-diabetic agent, which blocks mitochondria oxidative phosphorylation complex I, became the poster child agent to elicit AMPK activity and tumor suppression. Metformin sensitizes NSCLC models to chemotherapy and radiation. Here, we discuss the rationale for targeting metabolism, the evidence supporting metformin as an anti-tumor agent and adjunct to cytotoxic therapy in NSCLC and we review retrospective evidence and on-going clinical trials addressing this concept.

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