Previous studies revealed several mechanisms of acquired resistance to EGFR inhibitors in lung cancer such as EGFR T790 M mutation, MET amplification, IGF-1R upregulation, AXL upregulation, or histologic changes like transformation to small-cell lung cancer or EMT [35].However, the mechanisms of acquired resistance to EGFR-targeted therapy in an ESCC setting, where EGFR is wild-type, are poorly understood. Here, EGFR is linked to esophageal squamous cell carcinoma.