title: Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells.
abstract: BACKGROUND
  Up to 10 % of primary gastric cancers are characterized by FGFR2 amplification, and fibroblast growth factor receptor (FGFR) inhibitors may represent therapeutic agents for patients with these malignancies. However, long-term benefits of the treatment might be limited owing to the occurrence of drug resistance.
  
  
  METHODS
  To investigate the mechanisms of resistance to selective FGFR inhibitors, we established three FGFR2-amplified SNU-16 gastric cancer cell lines resistant to AZD4547, BGJ398, and PD173074, respectively.
  
  
  RESULTS
  The resistant cell lines (SNU-16R) demonstrated changes characteristic of epithelial-to-mesenchymal transition (EMT). In addition, they displayed loss of expression of FGFR2 and other tyrosine kinase receptors concurrent with activation of downstream signaling proteins and upregulation of the transforming growth factor β (TGF-β) level. However, treatment of parental SNU-16 cells with TGF-β1 did not evoke EMT, and pharmacological inhibition of TGF-β receptor I was not sufficient to reverse EMT changes in the resistant cells. Finally, we showed that the SNU-16R cell lines were sensitive to the human epidermal growth factor receptor 2 inhibitor mubritinib and the heat shock protein 90 inhibitor AUY922.
  
  
  CONCLUSIONS
  In conclusion, we provide experimental evidence that EMT-mediated resistance might emerge in gastric cancer patients following treatment with FGFR inhibitors, and mubritinib or AUY922 treatment may be an alternative therapeutic strategy for these patients.
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland. paulina.grygielewicz@celonpharma.com.|Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091, Warsaw, Poland. paulina.grygielewicz@celonpharma.com.
authors.forename: Paulina
authors.initials: P
authors.lastname: Grygielewicz
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dymek
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.|Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Bujak
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.|Department of Medical Biotechnology, Medical University of Lodz, Al. Kosciuszki 4, 90-419, Łodz, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Gunerka
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Stanczak
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Lamparska-Przybysz
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Wieczorek
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.|Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Banacha 1a, F Building, 02-097, Warsaw, Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Dzwonek
authors.affiliation: Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
authors.forename: Daria
authors.initials: D
authors.lastname: Zdzalik
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D058990:Molecular Targeted Therapy / Q000379:methods; D010080:Oxazoles / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D012118:Resorcinols / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D007555:Isoxazoles; D010080:Oxazoles; C115711:PD 173074; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D017468:Receptors, Fibroblast Growth Factor; D012118:Resorcinols; C000607331:TAK-165; D053773:Transforming Growth Factor beta1; D014230:Triazoles; C568950:infigratinib; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2
keywords: AZD4547; BGJ398; Drug resistance; Epithelial–mesenchymal transition; Fibroblast growth factor receptor; Fibroblast growth factor receptor inhibitor