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Antitumor Effect Of AZD4547 In A Fibroblast Growth Factor Receptor 2–Amplified Gastric Cancer Patient–Derived Cell Model1

Jiryeon Jang, H. Kim, Heejin Bang, S. Kim, S. Kim, S. Park, H. Lim, W. Kang, J. Lee, K. Kim
Published 2017 · Biology, Medicine

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BACKGROUND: FGFR2 amplification is associated with aggressive gastric cancer (GC), and targeted drugs have been developed for treatment of GC. We evaluated the antitumor activity of an FGFR inhibitor in FGFR2-amplified GC patients with peritoneal carcinomatosis. METHODS: Two GC patients with FGFR2 amplification confirmed by fluorescence in situ hybridization showed peritoneal seeding and malignant ascites. We used the patient-derived xenograft model; patient-derived cells (PDCs) from malignant ascites were used to assess FGFR2 expression and its downstream pathway using immunofluorescence analysis and immunoblot assay in vitro. Apoptosis and cell cycle arrest after treatment of FGFR inhibitor were analyzed by Annexin V-FITC assay and cell cycle analysis. RESULTS: FGFR2 amplification was verified in both PDC lines. AZD4547 as an FGFR inhibitor decreased proliferation of PDCs, and the IC50 value was estimated to be 250 nM in PDC#1 and 210 nM in PDC#2. FGFR inhibitor also significantly decreased levels of phosphorylated FGFR2 and downstream signaling molecules in FGFR2-amplified PDC lines. In cell cycle analysis, apoptosis was significantly increased in AZD4547-treated cells compared with nontreated cells. The proportion of cells in the sub-G1 stage was significantly higher in AZD4547-treated PDCs than in control cells. CONCLUSION: Our findings suggest that FGFR2 amplification is a relevant therapeutic target in GC with peritoneal carcinomatosis.
This paper references
10.3322/caac.21166
Cancer statistics, 2013
R. Siegel (2013)
10.1126/science.1220834
Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma
Devendra Singh (2012)
10.1016/0960-7404(92)90034-I
Risk factors which predict pattern of recurrence after curative surgery for patients with advanced gastric cancer.
S. Moriguchi (1992)
10.1002/(SICI)1097-0142(20000115)88:2<358::AID-CNCR16>3.0.CO;2-O
Peritoneal carcinomatosis from non‐gynecologic malignancies
B. Sadeghi (2000)
10.1158/1078-0432.CCR-12-3898
FGFR2 Gene Amplification in Gastric Cancer Predicts Sensitivity to the Selective FGFR Inhibitor AZD4547
L. Xie (2013)
Prognostic factors in patients with advanced gastric cancer treated by noncurative resection: a multivariate analysis.
S. Tsujitani (2001)
10.1002/wdev.176
The Fibroblast Growth Factor signaling pathway
D. Ornitz (2015)
10.1186/s13046-015-0276-9
Molecular targeted therapy for the treatment of gastric cancer
W. Xu (2016)
Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers.
J. H. Jang (2001)
10.1111/cge.12408
Innovative personalized medicine in gastric cancer: time to move forward
J. Lee (2014)
10.1016/j.tips.2016.10.003
Therapeutics Targeting FGF Signaling Network in Human Diseases.
M. Katoh (2016)
10.1136/bmj.1.5450.1567
Epidemiology of Stomach Cancer
T. Hirayama (1968)
10.3892/OR_00000297
Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma.
T. Toyokawa (2009)
10.1038/nrclinonc.2012.61
Patient-derived tumour xenografts as models for oncology drug development
J. Tentler (2012)
10.1158/0008-5472.CAN-07-5229
FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival.
K. Kunii (2008)
10.1200/JCO.2016.34.15_SUPPL.2502
Antitumor activity and safety of FPA144, an ADCC-enhanced, FGFR2b isoform-selective monoclonal antibody, in patients with FGFR2b+ gastric cancer and advanced solid tumors.
J. Lee (2016)
10.1038/nrc2780
Fibroblast growth factor signalling: from development to cancer
N. Turner (2010)
10.3322/canjclin.49.1.33
Global cancer statistics
D. Parkin (1999)
10.1002/med.21288
FGF Receptors: Cancer Biology and Therapeutics
M. Katoh (2014)
10.1007/BF02573875
Recurrence patterns after radical gastrectomy for gastric cancer: Prognostic factors and implications for postoperative adjuvant therapy
R. Schwarz (2002)
10.1200/JCO.2016.34.15_SUPPL.2016
Comprehensive mutation analysis in NRG Oncology/RTOG 9813: A phase III trial of RT + TMZ vs RT + nu for anaplastic astrocytoma and mixed anaplastic oligoastrocytoma (Astrocytoma Dominant).
E. H. Bell (2016)
10.4251/wjgo.v2.i2.85
Multidisciplinary therapy for treatment of patients with peritoneal carcinomatosis from gastric cancer.
Y. Yonemura (2010)
10.1158/0008-5472.CAN-11-3034
AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family.
P. Gavine (2012)
10.3322/caac.21262
Global cancer statistics, 2012
L. Torre (2015)
10.1158/0008-5472.CAN-05-1855
Somatic mutations of the protein kinase gene family in human lung cancer.
Helen Davies (2005)
10.1158/1078-0432.CCR-06-1164
FGFR1 Emerges as a Potential Therapeutic Target for Lobular Breast Carcinomas
J. Reis-Filho (2006)
10.1016/j.humpath.2011.12.002
Fibroblast growth factor receptor 2 gene amplification status and its clinicopathologic significance in gastric carcinoma.
Eun-jung Jung (2012)
10.18632/oncotarget.10740
Metastatic spread in patients with gastric cancer
M. Riihimäki (2016)
10.1038/bjc.2013.802
FGFR2 amplification has prognostic significance in gastric cancer: results from a large international multicentre study
X. Su (2014)
10.1126/scitranslmed.3001451
Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer
J. Weiss (2010)
10.1158/1078-0432.CCR-12-2694
Translating the Therapeutic Potential of AZD4547 in FGFR1-Amplified Non–Small Cell Lung Cancer through the Use of Patient-Derived Tumor Xenograft Models
Jingchuan Zhang (2012)
10.1002/path.1202
Frequent FGFR3 mutations in urothelial papilloma
B. V. van Rhijn (2002)
10.1200/JCO.2015.33.15_SUPPL.2015
Onartuzumab plus bevacizumab versus placebo plus bevacizumab in recurrent glioblastoma (GBM): HGF and MGMT biomarker data.
T. Cloughesy (2015)
10.1158/1078-0432.CCR-11-0699
Molecular Pathways: Fibroblast Growth Factor Signaling: A New Therapeutic Opportunity in Cancer
A. N. Brooks (2012)
10.1158/1078-0432.CCR-14-3212
The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing
T. Helsten (2015)
10.1093/annonc/mdt419
Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.
R. Dienstmann (2014)
10.1200/JCO.2015.33.15_SUPPL.4014
A randomized, open-label phase II study of AZD4547 (AZD) versus Paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with Fibroblast Growth Factor Receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study.
Y. Bang (2015)
10.1158/0008-5472.CAN-13-1069
Patient-derived tumor xenografts: transforming clinical samples into mouse models.
Despina Siolas (2013)
10.1007/s004320000128
Up-regulation and co-expression of fibroblast growth factor receptors in human gastric cancer
E. Shin (2000)
10.3322/caac.20107
Global cancer statistics
A. Jemal (2011)
10.1002/ijc.28373
Peritoneal carcinomatosis of gastric origin: A population‐based study on incidence, survival and risk factors
I. Thomassen (2014)



This paper is referenced by
10.1007/s10753-019-01056-4
Inhibition of Fibroblast Growth Factor Receptor by AZD4547 Protects Against Inflammation in Septic Mice
Yueyue Huang (2019)
10.1080/13543784.2019.1672655
Investigational fibroblast growth factor receptor 2 antagonists in early phase clinical trials to treat solid tumors
D. Wang (2019)
Paper miR-671-5 p Blocks The Progression Of Human Esophageal Squamous Cell Carcinoma By Suppressing FGFR 2
X. Li (2019)
10.1080/14737140.2018.1491795
Future applications of FGF/FGFR inhibitors in cancer
G. C. Ghedini (2018)
10.7754/Clin.Lab.2018.180330
NOB1 Gene as a Potential Biomarker in Clinical Outcomes and Prognosis of Patients with Gastric Cancer.
H. Qi (2018)
10.1038/s41571-018-0115-y
Fibroblast growth factor receptors as treatment targets in clinical oncology
M. Katoh (2018)
10.1634/theoncologist.2019-0121
FGFR2‐Altered Gastroesophageal Adenocarcinomas Are an Uncommon Clinicopathologic Entity with a Distinct Genomic Landscape
S. Klempner (2019)
10.1371/journal.pone.0215080
Selective colony area method for heterogeneous patient-derived tumor cell lines in anti-cancer drug screening system
J. Cho (2019)
10.1007/s10637-020-00933-2
Mechanisms of Efficacy of the FGFR1–3 Inhibitor AZD4547 in Pediatric Solid Tumor Models
Nikki Phanhthilath (2020)
10.1016/j.cytogfr.2019.03.002
Exploitation of phage display for the development of anti-cancer agents targeting fibroblast growth factor signaling pathways: New strategies to tackle an old challenge.
B. Jafari (2019)
10.3390/cells8060637
Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis
Jinglin Zhang (2019)
10.1016/j.lungcan.2019.12.018
A phase II trial of single oral FGF inhibitor, AZD4547, as second or third line therapy in malignant pleural mesothelioma.
Wei-Sen Lam (2019)
10.1038/s41388-020-01458-x
FGF18–FGFR2 signaling triggers the activation of c-Jun–YAP1 axis to promote carcinogenesis in a subgroup of gastric cancer patients and indicates translational potential
Jinglin Zhang (2020)
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