Scientific Publications

Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization.

Publication TypeJournal Article
AuthorsCho, J., Chen L., Sangji N., Okabe T., Yonesaka K., Francis JM, Flavin RJ, Johnson W., Kwon J., Yu S., Greulich HE, Johnson B. E., Eck MJ, Janne PA, Wong KK, and Meyerson M.
AbstractKinase 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.
Year of Publication2013
JournalCancer research
Date Published (YYYY/MM/DD)2013/09/24
ISSN Number0008-5472
DOI10.1158/0008-5472.CAN-13-1145
PubMedhttp://www.ncbi.nlm.nih.gov/pubmed/24063894?dopt=Abstract