Over 40% of EGFR TKI resistance cases now originate from tumor cells abandoning EGFR dependency through: (1) Bypass activation, including MET amplification-mediated ERBB3-PI3K/AKT signaling, HER2/HER3 heterodimer-driven MAPK activation and AXL-RTK-mediated EMT [34–36], or (2) Downstream mutations (e.g., KRAS G12C/BRAF V600E) that bypass EGFR regulation [37], or (3) Phenotypic plasticity through tumor stem cell maintenance via WNT/Notch pathways or metabolic reprogramming (e.g., glutamine dependency) [38, 39]. This evidence concerns the gene AKT1 and neoplasm.