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

Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells.

Author information

1
Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland. paulina.grygielewicz@celonpharma.com.
2
Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091, Warsaw, Poland. paulina.grygielewicz@celonpharma.com.
3
Innovative Drugs R&D Department, Celon Pharma Inc., Mokra 41a, 05-092, Lomianki/Kielpin, Poland.
4
Postgraduate School of Molecular Medicine, Zwirki i Wigury 61, 02-091, Warsaw, Poland.
5
Department of Medical Biotechnology, Medical University of Lodz, Al. Kosciuszki 4, 90-419, Łodz, Poland.
6
Department of Immunology, Center for Biostructure Research, Medical University of Warsaw, Banacha 1a, F Building, 02-097, Warsaw, Poland.

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

PMID:
25407459
PMCID:
PMC4688307
DOI:
10.1007/s10120-014-0444-1
[Indexed for MEDLINE]
Free PMC Article

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