Purpose To investigate the mechanism of pretreatment with EGFR inhibitors sensitizes cancer cells to DNA-damaging therapy.Method MTT assay was applyed to detect inhibition of cell proliferation by EGFR inhibitors and Doxocubicin alone or in combination.Western blot analysis was used to detect the protein levels.Native-page was used to detect the formation of dimer.Immunoprecipitation was employed to determine the protein-protein interactions.Results & Conclusion In this work, we found that pretreatment with EGFR inhibitors mediated caspase-8 homodimerization ,which sensitizes cancer cells to DNA-damaging therapy.ERK plays an important role in sequential application of anticancer drugs.P-ERK can phosphorylate caspase-8 at its S387 residue.