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) |