Are metformin-based combination approaches beneficial for non-small cell lung cancer: evidence from experimental and clinical studies

Abstract Despite having multiple treatment options, the overall outcomes, including the survival rates of non-small cell lung cancer (NSCLC) patients, remain relatively low, indicating the need to explore new approaches to achieve improved therapeutic responses. To that end, repurposed drugs such as metformin have been evaluated against many cancer types, including NSCLC. Metformin, a widely used oral hypoglycemic drug for type 2 diabetes, exhibits anticancer properties and synergy with several standards of care agents. In this review, we provide a comprehensive overview of the role and anticancer mechanisms of metformin-based combination approaches for the treatment of NSCLC. We logically discussed the experimental evidence from the in vitro and in vivo studies utilizing metformin alone, and then its combination with chemotherapeutic agents, targeted therapy, and immunotherapy. We also present clinical trials that underscore the beneficial and adverse outcomes of metformin use in combination with targeted therapy and chemotherapeutic agents, and emphasize the limitations and challenges for the treatment of diabetic and non-diabetic NSCLC patients. It appears that, regardless of the diverse anticancer mechanisms of this biguanide, the benefits may be confined to a specific patient subgroup, which opens new avenues to be explored for NSCLC treatment.