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Cancer Res DOI:10.1158/0008-5472.CAN-13-1145

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

Publication TypeJournal Article
Year of Publication2013
AuthorsCho, J, Chen, L, Sangji, N, Okabe, T, Yonesaka, K, Francis, JM, Flavin, RJ, Johnson, W, Kwon, J, Yu, S, Greulich, H, Johnson, BE, Eck, MJ, Jänne, PA, Wong, K-K, Meyerson, M
JournalCancer Res
Date Published2013 Nov 15
KeywordsAdenocarcinoma, Amino Acid Substitution, Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cell Transformation, Neoplastic, Cells, Cultured, Cetuximab, Humans, Lung Neoplasms, Mice, NIH 3T3 Cells, Protein Conformation, Protein Multimerization, Receptor, Epidermal Growth Factor

Kinase domain mutations of the EGF 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 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. 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.


Alternate JournalCancer Res.
PubMed ID24063894
PubMed Central IDPMC3903789
Grant ListP01 CA154303 / CA / NCI NIH HHS / United States
R01 CA116020 / CA / NCI NIH HHS / United States