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学科主题: 临床医学
题名:
FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547
作者: Xie, Liang1; Su, Xinying1; Zhang, Lin1; Yin, Xiaolu1; Tang, Lili1; Zhang, Xiuhua1; Xu, Yanping1; Gao, Zeren1; Liu, Kunji1; Zhou, Minhua1; Gao, Beirong1; Shen, Danping2; Zhang, Lianhai3; Ji, Jiafu3; Gavine, Paul R.1; Zhang, Jingchuan1; Kilgour, Elaine4; Zhang, Xiaolin1; Ji, Qunsheng1
刊名: CLINICAL CANCER RESEARCH
发表日期: 2013-05-01
DOI: 10.1158/1078-0432.CCR-12-3898
卷: 19, 期:9, 页:2572-2583
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Oncology
研究领域[WOS]: Oncology
关键词[WOS]: GROWTH-FACTOR RECEPTOR-2 ; CELL LUNG-CANCER ; SOMATIC MUTATIONS ; BREAST-CANCER ; PATTERNS ; THERAPY ; FAMILY ; TRASTUZUMAB ; RESISTANCE ; CARCINOMA
英文摘要:

Purpose: FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer and the therapeutic potential of AZD4547, a potent and selective ATP-competitive receptor tyrosine kinase inhibitor of fibroblast growth factor receptor (FGFR) 1-3, in patients with FGFR2-amplified gastric cancer.

Experimental Design: Array-comparative genomic hybridization and FISH were used to identify FGFR2 amplification in gastric cancer patient tumor samples. The effects of FGFR2 modulation were investigated in gastric cancer cells with FGFR2 amplification and in patient-derived gastric cancer xenograft (PDGCX) models using two approaches: inhibition with AZD4547 and short hairpin RNA (shRNA) knockdown of FGFR2.

Results: Amplification of the FGFR2 gene was identified in a subset of Chinese and Caucasian patients with gastric cancer. Gastric cancer cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI(50) values of 3 and 5 nmol/L, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083) but not in nonamplified models. shRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared with monotherapy, we showed enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents.

Conclusion: FGFR2 pathway activation is required for driving growth and survival of gastric cancer carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with gastric cancer carrying FGFR2 gene amplification. Clin Cancer Res; 19(9); 2572-83. (C) 2013 AACR.

语种: 英语
项目资助者: AstraZeneca
WOS记录号: WOS:000318361900030
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/66088
Appears in Collections:北京大学临床肿瘤学院_肿瘤外科_期刊论文

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作者单位: 1.Shanghai Jiao Tong Univ, Sch Med, Renji Hosp, Shanghai 200030, Peoples R China
2.Peking Univ, Dept Surg, Key Lab Carcinogenesis & Translat Res, Beijing Inst Canc Res,Canc Hosp,Minist Educ, Beijing 100871, Peoples R China
3.AstraZeneca R&D, Innovat Ctr China, Shanghai, Peoples R China
4.AstraZeneca Oncol, Macclesfield, Cheshire, England

Recommended Citation:
Xie, Liang,Su, Xinying,Zhang, Lin,et al. FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547[J]. CLINICAL CANCER RESEARCH,2013,19(9):2572-2583.
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