S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells
- Kim, Hwang-Phill; Han, Sae-Won; Kim, Sung-Hak; Im, Seock-Ah; Oh, Do-Youn; Bang, Yung-Jue; Kim, Tae-You
- Issue Date
- American Association for Cancer Research
- Molecular Cancer Therapeutics, Vol.7 No.3, pp.607-615
- Animals; Antibodies, Monoclonal/*pharmacology; Antineoplastic Agents/*pharmacology; COS Cells; Carcinoma, Non-Small-Cell Lung/*pathology; Cell Line, Tumor; Cercopithecus aethiops; Dimerization; Drug Resistance, Neoplasm/genetics; Genes, erbB-2; Humans; Lung Neoplasms/*pathology; Mutation; Quinazolines/*pharmacology; Receptor, Epidermal Growth Factor/antagonists & inhibitors/chemistry
- 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.
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