| RRC ID |
37072
|
| 著者 |
Yonesaka K, Hirotani K, Kawakami H, Takeda M, Kaneda H, Sakai K, Okamoto I, Nishio K, Jänne PA, Nakagawa K.
|
| タイトル |
Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib.
|
| ジャーナル |
Oncogene
|
| Abstract |
Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.
|
| 巻・号 |
35(7)
|
| ページ |
878-86
|
| 公開日 |
2016-2-18
|
| DOI |
10.1038/onc.2015.142
|
| PII |
onc2015142
|
| PMID |
25961915
|
| MeSH |
Animals
Antibodies, Monoclonal / pharmacology*
Antibodies, Monoclonal, Humanized
Antibodies, Neutralizing / pharmacology*
Antineoplastic Agents / pharmacology*
Blotting, Western
Broadly Neutralizing Antibodies
Carcinoma, Non-Small-Cell Lung* / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects*
ErbB Receptors / antagonists & inhibitors
Erlotinib Hydrochloride / pharmacology
Female
Heterografts
Humans
Lung Neoplasms* / metabolism
Mice
Neuregulin-1 / metabolism
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Receptor, ErbB-3 / antagonists & inhibitors
Transfection
|
| IF |
7.971
|
| 引用数 |
47
|
|
WOS 分野
|
GENETICS & HEREDITY
ONCOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
EBC-1(RCB1965)
Sq-1(RCB1905)
RERF-LC-AI(RCB0444) |
