title: Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers.
abstract: Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) were identified in approximately 15% of all patients with non-small cell lung cancer (NSCLC). These mutations have been established as an indicator of superior response to gefitinib and erlotinib, small molecule inhibitors of the EGFR kinase domain. Whether these mutations would also render patients more susceptible to treatment with cetuximab (Erbitux), an EGFR-neutralizing antibody, is yet to be determined. In this study, we attempted to evaluate the effect of cetuximab on several NSCLC lines harboring some of the more common EGFR mutations (L858R and delL747-T753insS), as well as the recently identified kinase inhibitor-resistant mutation, T790M. We could show that the kinase activity of the abovementioned EGFR mutants was hindered by cetuximab, as detected by both cell-based phosphorylation and proliferation assays. Interestingly, cetuximab also induced enhanced degradation of the EGFR mutants as compared with the wild-type receptor. Most importantly, cetuximab successfully inhibited the growth of NSCLC lines in xenograft models. These results indicate the promising potential of cetuximab as a regimen for patients with NSCLC bearing these mutations.
authors.affiliation: ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA.
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Doody
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Sheetal N
authors.initials: SN
authors.lastname: Patel
authors.forename: Christopher
authors.initials: C
authors.lastname: Joynes
authors.forename: Sui Ping
authors.initials: SP
authors.lastname: Lee
authors.forename: Jason
authors.initials: J
authors.lastname: Gerlak
authors.forename: Robin L
authors.initials: RL
authors.lastname: Rolser
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.forename: Philipp
authors.initials: P
authors.lastname: Steiner
authors.forename: Rajiv
authors.initials: R
authors.lastname: Bassi
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Hicklin
authors.forename: Yaron R
authors.initials: YR
authors.lastname: Hadari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019281:Dimerization; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D025801:Ubiquitin; D066246:ErbB Receptors; D000068818:Cetuximab