Epithelial-mesenchymal Transition Confers Resistance to Selective FGFR Inhibitors in SNU-16 Gastric Cancer Cells

Gastric Cancer. 2016 Jan;19(1):53-62. doi: 10.1007/s10120-014-0444-1. Epub 2014 Nov 19.

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.

Conclusion: 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.

Keywords: AZD4547; BGJ398; Drug resistance; Epithelial–mesenchymal transition; Fibroblast growth factor receptor; Fibroblast growth factor receptor inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzamides / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Epithelial-Mesenchymal Transition / drug effects*
  • Humans
  • Isoxazoles / pharmacology
  • Molecular Targeted Therapy / methods
  • Oxazoles / pharmacology
  • Phenylurea Compounds / pharmacology
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors
  • Receptor, Fibroblast Growth Factor, Type 2 / genetics
  • Receptor, Fibroblast Growth Factor, Type 2 / metabolism
  • Receptors, Fibroblast Growth Factor / antagonists & inhibitors
  • Resorcinols / pharmacology
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / pathology
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta1 / pharmacology
  • Triazoles / pharmacology

Substances

  • 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-(4-(4-ethylpiperazin-1-yl)-phenylamino)pyrimidin-4-yl)-1-methylurea
  • 5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide
  • AZD4547
  • Antineoplastic Agents
  • Benzamides
  • Isoxazoles
  • Oxazoles
  • PD 173074
  • Phenylurea Compounds
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Receptors, Fibroblast Growth Factor
  • Resorcinols
  • TAK-165
  • Transforming Growth Factor beta1
  • Triazoles
  • FGFR2 protein, human
  • Receptor, Fibroblast Growth Factor, Type 2