Indeed, while sensitizing EGFR-mutations are prevalently occurring as early clonal events during NSCLC development, most advanced NSCLCs possess heterogeneous regions harboring late clonal driver alterations that can represent TKI-resistance mechanisms, such as mutations in TP53 and genes involved in the RAS-RAF-MAPK or PI3K-AKT-PTEN-mTOR pathways, cell cycle regulation, Wnt/β-catenin pathway, DNA damage repair, chromatin remodeling, and histone methylation [11,12]. This evidence concerns the gene PTEN and non-small cell lung carcinoma.