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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
2008-03-19
Publisher
American Association for Cancer Research
Citation
Mol Cancer Ther. 2008;7(3):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 for threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We 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 (Print)
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

http://hdl.handle.net/10371/68253
DOI
https://doi.org/10.1158/1535-7163.MCT-07-2068
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College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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