Epidermal growth factor receptor tyrosine-kinase inhibitor treatment resistance in non-small cell lung cancer: biological basis and therapeutic strategies

Lung cancer remains the leading cause of cancer-related death. Non-small cell lung cancer (NSCLC) represents 85 % of all lung cancer cases and it is classified into three major subtypes: adenocarcinoma, squamous cell carcinoma and large-cell carcinoma. In the past years, molecular-targeted therapies have been developed in order to improve response, survival and quality of life in patients with advanced NSCLC. Lung cancers harboring mutations in the epidermal growth factor receptor (EGFR) respond to EGFR tyrosine-kinase inhibitors (TKIs). However, virtually all patients with initial response relapse due to acquired resistance. Better understanding the biology of these tumors and mechanisms of EGFR TKIs resistance could shed some light on research of new therapeutic options in this setting. This review aims to emphasize on EGFR involved lung cancer pathway, primary and acquired mechanisms of TKIs resistance, and discuss agents currently used in clinical development in this emerging scenario.