In summary, our study revealed that the EGFR/HER2 inhibitors gefitinib and lapatinib, in combination with the IGF-1R inhibitor linsitinib, have synergistic effects on the inhibition of proliferation, the cell cycle arrest, the apoptosis, the invasion, and the migration of ESCC cells in vitro, as well as on tumor growth in vivo. The gene discussed is ERBB2; the disease is esophageal squamous cell carcinoma.