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Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers.
Mol Cancer Ther 2007; 6(10):2642-51MC

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+Show Affiliations

ImClone Systems Incorporated, 180 Varick Street, New York, NY 10014, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17913857

Citation

Doody, Jacqueline F., et al. "Inhibitory Activity of Cetuximab On Epidermal Growth Factor Receptor Mutations in Non Small Cell Lung Cancers." Molecular Cancer Therapeutics, vol. 6, no. 10, 2007, pp. 2642-51.
Doody JF, Wang Y, Patel SN, et al. Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers. Mol Cancer Ther. 2007;6(10):2642-51.
Doody, J. F., Wang, Y., Patel, S. N., Joynes, C., Lee, S. P., Gerlak, J., ... Hadari, Y. R. (2007). Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers. Molecular Cancer Therapeutics, 6(10), pp. 2642-51.
Doody JF, et al. Inhibitory Activity of Cetuximab On Epidermal Growth Factor Receptor Mutations in Non Small Cell Lung Cancers. Mol Cancer Ther. 2007;6(10):2642-51. PubMed PMID: 17913857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibitory activity of cetuximab on epidermal growth factor receptor mutations in non small cell lung cancers. AU - Doody,Jacqueline F, AU - Wang,Ying, AU - Patel,Sheetal N, AU - Joynes,Christopher, AU - Lee,Sui Ping, AU - Gerlak,Jason, AU - Rolser,Robin L, AU - Li,Yanxia, AU - Steiner,Philipp, AU - Bassi,Rajiv, AU - Hicklin,Dan J, AU - Hadari,Yaron R, Y1 - 2007/10/03/ PY - 2007/10/5/pubmed PY - 2008/2/8/medline PY - 2007/10/5/entrez SP - 2642 EP - 51 JF - Molecular cancer therapeutics JO - Mol. Cancer Ther. VL - 6 IS - 10 N2 - 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. SN - 1535-7163 UR - https://www.unboundmedicine.com/medline/citation/17913857/Inhibitory_activity_of_cetuximab_on_epidermal_growth_factor_receptor_mutations_in_non_small_cell_lung_cancers_ L2 - http://mct.aacrjournals.org/cgi/pmidlookup?view=long&pmid=17913857 DB - PRIME DP - Unbound Medicine ER -