FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547
| Autor: | Danping Shen, Xiaolin Zhang, Paul R. Gavine, Kunji Liu, Xiuhua Zhang, Minhua Zhou, Yanping Xu, Lin Zhang, Jingchuan Zhang, Elaine Kilgour, Liang Xie, Xinying Su, Jiafu Ji, Xiaolu Yin, Zeren Gao, Lili Tang, Lianhai Zhang, Beirong Gao, Qunsheng Ji |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Cancer Research Apoptosis Docetaxel Piperazines Small hairpin RNA Mice Antineoplastic Combined Chemotherapy Protocols Gene Knockdown Techniques RNA Small Interfering Aged 80 and over Gene knockdown Mice Inbred BALB C integumentary system Drug Synergism Middle Aged Treatment Outcome Oncology Fibroblast growth factor receptor embryonic structures Benzamides Female Taxoids Fluorouracil Signal Transduction musculoskeletal diseases Adult congenital hereditary and neonatal diseases and abnormalities Adolescent Mice Nude Biology Irinotecan Inhibitory Concentration 50 Young Adult In vivo Stomach Neoplasms Cell Line Tumor medicine Animals Humans Receptor Fibroblast Growth Factor Type 2 Aged Gene Amplification Cancer FGFR Inhibitor AZD4547 medicine.disease Molecular biology Xenograft Model Antitumor Assays stomatognathic diseases Case-Control Studies Cancer cell Pyrazoles Camptothecin Cisplatin |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 19(9) |
| ISSN: | 1557-3265 |
| Popis: | 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 GI50 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. ©2013 AACR. |
| Databáze: | OpenAIRE |
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