Browse

Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells

Cited 52 time in Web of Science Cited 52 time in Scopus
Authors
Kim, Hwang-Phill; Han, Sae-Won; Kim, Sung-Hak; Im, Seock-Ah; Oh, Do-Youn; Bang, Yung-Jue; Kim, Tae-You
Issue Date
2008-03
Publisher
American Association for Cancer Research
Citation
Molecular Cancer Therapeutics, Vol.7 No.3, pp.607-615
Keywords
AnimalsAntibodies, Monoclonal/*pharmacologyAntineoplastic Agents/*pharmacologyCOS CellsCarcinoma, Non-Small-Cell Lung/*pathologyCell Line, TumorCercopithecus aethiopsDimerizationDrug Resistance, Neoplasm/geneticsGenes, erbB-2HumansLung Neoplasms/*pathologyMutationQuinazolines/*pharmacologyReceptor, Epidermal Growth Factor/antagonists & inhibitors/chemistry
Abstract
Although non-small cell lung cancer (NSCLC) cells with somatic mutations in their epidermal growth factor receptors (EGFR) initially show a dramatic response to tyrosine kinase inhibitor (TKI), these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine or threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. e observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC.
ISSN
1535-7163
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18347147

http://mct.aacrjournals.org/content/7/3/607.full.pdf

https://hdl.handle.net/10371/68253
DOI
https://doi.org/10.1158/1535-7163.MCT-07-2068
Files in This Item:
There are no files associated with this item.
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse