RRC ID 45382
著者 Watanuki Z, Kosai H, Osanai N, Ogama N, Mochizuki M, Tamai K, Yamaguchi K, Satoh K, Fukuhara T, Maemondo M, Ichinose M, Nukiwa T, Tanaka N.
タイトル Synergistic cytotoxicity of afatinib and cetuximab against EGFR T790M involves Rab11-dependent EGFR recycling.
ジャーナル Biochem Biophys Res Commun
Abstract EGFR is an important therapeutic target for non-small cell lung cancers (NSCLCs). Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, are effective in cases with EGFR-activating mutations. However, most such cases become resistant through a secondary EGFR mutation, T790M. While the second-generation TKI afatinib has a higher affinity for double-mutant EGFRs, better efficacy is needed. Combining afatinib with the anti-EGFR monoclonal antibody cetuximab improves clinical outcomes, but the mechanism is unclear. Here we examined this effect using erythroleukemic K562 cells. The activating EGFR mutation L858R is sensitive to first-generation TKIs, and adding T790M confers resistance to these drugs. This double-mutant EGFR was moderately sensitive to afatinib, but responded weakly to cetuximab. Combined afatinib and cetuximab synergistically increased their cytotoxicity for K562 cells expressing the double-mutant EGFR. Apoptosis in these cells followed induction of the pro-apoptotic protein BIM. Unexpectedly, afatinib caused redistribution of EGFR to the cell surface through Rab11a-dependent recycling. Cetuximab reduced cell-surface EGFR, and total EGFR decreased synergistically when cetuximab was combined with afatinib. Our results suggest that the synergistic effect exerted by afatinib and cetuximab on NSCLCs is associated with BIM induction and alterations in EGFR status.
巻・号 455(3-4)
ページ 269-76
公開日 2014-12-12
DOI 10.1016/j.bbrc.2014.11.003
PII S0006-291X(14)01996-2
PMID 25446083
MeSH Afatinib Animals Antibodies, Monoclonal / chemistry Antibodies, Monoclonal, Humanized / pharmacology* Antineoplastic Agents / pharmacology* Apoptosis Apoptosis Regulatory Proteins / metabolism Bcl-2-Like Protein 11 COS Cells Cell Membrane / metabolism Cetuximab Chlorocebus aethiops Dose-Response Relationship, Drug Drug Resistance, Neoplasm ErbB Receptors / genetics ErbB Receptors / metabolism* HeLa Cells Humans K562 Cells Membrane Proteins / metabolism Microscopy, Confocal Microscopy, Fluorescence Mutation Proto-Oncogene Proteins / metabolism Quinazolines / pharmacology* rab GTP-Binding Proteins / metabolism*
IF 2.985
引用数 17
WOS 分野 BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 K562 HeLa COS-7(RCB0539)