Asymmetric dimerization of the kinase domain is a key mechanism for activation of the epidermal growth factor receptor (EGFR). Here, we show that whereas wild‐type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization. Consistent with these findings, tyrosine phosphorylation of the carboxyl‐terminus is not required for mutant EGFR‐mediated cellular transformation. These differences in dimerization requirements may have clinical implications: treatment with the monoclonal antibody, cetuximab, shrinks mouse lung tumors induced by the dimerization‐dependent L858R mutant, but exerts only a modest effect on tumors driven by dimerization‐independent EGFR mutants. These data imply that disruption of dimerization is among the antitumor mechanisms of cetuximab. We therefore hypothesize that EGFR mutation status in lung cancers may serve as a marker for clinical response to cetuximab.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A177.