Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization
Menée sur des modèles murins de cancer du poumon, cette étude montre que la réponse des tumeurs au cetuximab est associée à des mutations du gène EGFR nécessitant une dimérisation pour la transformation oncogénique
Kinase domain mutations of the epidermal growth factor receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that while 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. In addition, 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 different EGFR mutants show differential requirements for dimerization, and that disruption of dimerization may be among the antitumor mechanisms of cetuximab.
Cancer Research 2013