Cetuximab is the only anti-EGFR treatment approved for the treatment of head and neck tumors, however, an insufficient response rates have been reported in HNSCC patients. For this reason, in last years, a new class of anti-EGFR (afatinib and allitinib) with covalent and irreversible action to others members of EGFR family were designed. In our study, we demonstrated the higher efficiency of these irreversible inhibitors when compared to cetuximab. In addition, we found a persistent AKT phosphorylation in resistant cell lines treated with anti-EGFR inhibitors.