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Cancer Res. 2013 Nov 15;73(22):6770-9. doi: 10.1158/0008-5472.CAN-13-1145. Epub 2013 Sep 24.

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

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Authors' Affiliations: Departments of Medical Oncology and Cancer Biology; Center for Cancer Genome Discovery, Lowe Center for Thoracic Oncology, and Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute; Departments of Medicine, Brigham and Women's Hospital; Departments of Biological Chemistry and Molecular Pharmacology and Pathology, Harvard Medical School, Boston, Massachusetts; Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea; and The Broad Institute of Harvard and MIT, Cambridge, Massachusetts.


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.

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