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

Cited 53 time in Web of Science Cited 54 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
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
https://hdl.handle.net/10371/68253
DOI
https://doi.org/10.1158/1535-7163.MCT-07-2068
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  • Department of Medicine
Research Area Clinical Medicine

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