| RRC ID |
44533
|
| 著者 |
Ono N, Yamazaki T, Tsukaguchi T, Fujii T, Sakata K, Suda A, Tsukuda T, Mio T, Ishii N, Kondoh O, Aoki Y.
|
| タイトル |
Enhanced antitumor activity of erlotinib in combination with the Hsp90 inhibitor CH5164840 against non-small-cell lung cancer.
|
| ジャーナル |
Cancer Sci
|
| Abstract |
Inhibition of heat shock protein 90 (Hsp90) can lead to degradation of multiple client proteins, which are involved in tumor progression. Epidermal growth factor receptor (EGFR) is one of the most potent oncogenic client proteins of Hsp90. Targeted inhibition of EGFR has shown clinical efficacy in the treatment of patients with non-small-cell lung cancer (NSCLC). However, primary and acquired resistance to the existing EGFR inhibitors is a major clinical problem. In the present study, we investigated the effect of the novel Hsp90 inhibitor CH5164840 on the antitumor activity of erlotinib. The NSCLC cell lines and xenograft models were treated with CH5164840 and erlotinib to examine their mechanisms of action and cell growth inhibition. We found that CH5164840 showed remarkable antitumor activity against NSCLC cell lines and xenograft models. The addition of CH5164840 enhanced the antitumor activity of erlotinib against NCI-H292 EGFR-overexpressing xenograft models. Phosphorylation of Stat3 increased with erlotinib treatment in NCI-H292 cells, which was abrogated by Hsp90 inhibition. Furthermore, in a NCI-H1975 T790M mutation erlotinib-resistant model, CH5164840 enhanced the antitumor activity of erlotinib despite the low efficacy of erlotinib treatment alone. In addition, ERK signaling was effectively suppressed by combination treatment with erlotinib and CH5164840 in a NCI-H1975 erlotinib-resistant model. Taken together, these data indicate that CH5164840 has potent antitumor activity and is highly effective in combination with erlotinib against NSCLC tumors with EGFR overexpression and mutations. Our results support the therapeutic potential of CH5164840 as a Hsp90 inhibitor for combination therapy with EGFR-targeting agents against EGFR-addicted NSCLC.
|
| 巻・号 |
104(10)
|
| ページ |
1346-52
|
| 公開日 |
2013-10-1
|
| DOI |
10.1111/cas.12237
|
| PMID |
23863134
|
| PMC |
PMC7656539
|
| MeSH |
Animals
Benzoquinones / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor / drug effects
Drug Synergism
ErbB Receptors / antagonists & inhibitors*
Erlotinib Hydrochloride
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
Humans
Janus Kinase 1 / metabolism
Lactams, Macrocyclic / pharmacology*
Lung Neoplasms / drug therapy*
Lung Neoplasms / pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Transplantation
Phosphorylation / drug effects
Protein Processing, Post-Translational / drug effects
Quinazolines / pharmacology*
STAT3 Transcription Factor / antagonists & inhibitors
Xenograft Model Antitumor Assays
|
| IF |
4.966
|
| 引用数 |
25
|
|
WOS 分野
|
ONCOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
EBC-1(RCB1965) |
