title: FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Innovation Center China, AstraZeneca R&D, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.forename: Lili
authors.initials: L
authors.lastname: Tang
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Zhang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Xu
authors.forename: Zeren
authors.initials: Z
authors.lastname: Gao
authors.forename: Kunji
authors.initials: K
authors.lastname: Liu
authors.forename: Minhua
authors.initials: M
authors.lastname: Zhou
authors.forename: Beirong
authors.initials: B
authors.lastname: Gao
authors.forename: Danping
authors.initials: D
authors.lastname: Shen
authors.forename: Lianhai
authors.initials: L
authors.lastname: Zhang
authors.forename: Jiafu
authors.initials: J
authors.lastname: Ji
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Elaine
authors.initials: E
authors.lastname: Kilgour
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D001549:Benzamides / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D006801:Humans; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: C572463:AZD4547; D001549:Benzamides; D010879:Piperazines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D000077146:Irinotecan; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin