Targeting the Molecular Crosstalk Between Diabetes and Lung Cancer for Therapeutic Intervention Publisher



A Azani ALIREZA ; Na Avval Nahal AGHAJAMAL ; Mss Meigoli Mohammad Saeed SOLEIMANI ; M Imankhan MAHSHID ; P Asgari POUYA ; G Ebrahimisaraj GHOLAMREZA ; R Morovatshoar REZA ; Am Hosseini Ahmad MIR ; St Mirzohreh Seyedeh TARLAN ; M Nouri MASOUMEH
Source: Discover Oncology Published:2025

Abstract

Purpose: This review investigates the complex association between type 2 diabetes mellitus (T2DM) and lung cancer, focusing on shared risk factors, molecular mechanisms, and clinical implications. We aim to quantify the impact of T2DM on lung cancer incidence, progression, and treatment response, and evaluate the role of glycemic control and antidiabetic therapies. Methods: A narrative review was conducted following a targeted search of PubMed, Scopus, and Web of Science for published studies. Search terms included “type 2 diabetes mellitus,” “lung cancer,” “non-small cell lung cancer,” “hyperglycemia,” “insulin resistance,” and relevant synonyms. Inclusion criteria were original research articles, meta-analyses, and clinical trials involving human subjects that explored epidemiological associations, molecular mechanisms, pharmacologic interventions, or prognostic implications of T2DM in lung cancer. Studies focusing solely on type 1 diabetes, animal models, or non-English language were excluded. Key findings were synthesized to provide mechanistic insights and clinical relevance. Results: Epidemiological evidence indicates a 20–48% increased relative risk of lung cancer in individuals with T2DM, with incidence rates reaching 125 per 100,000 in diabetics versus 85 per 100,000 in non-diabetics. Shared risk factors include obesity, smoking, and physical inactivity. Molecular pathways such as K-Ras and PI3K/Akt activation, IGF-1R overexpression, and hyperglycemia-induced oxidative stress promote tumorigenesis and metastasis. Metformin is associated with reduced lung cancer incidence and improved progression-free survival (58% vs. 37% at 2 years). Pioglitazone and DPP4 inhibitors show potential benefits, though clinical evidence remains mixed. Conclusion: T2DM significantly influences lung cancer biology and prognosis. Integrating glycemic control with cancer therapy—particularly metformin and EGFR-TKI combinations—offers promising avenues for improving outcomes. Future research should focus on biomarker-driven stratification and targeted therapeutic strategies tailored to diabetic lung cancer patients. © 2025 Elsevier B.V., All rights reserved.