Document Detail


Epithelial-mesenchymal transition confers resistance to selective FGFR inhibitors in SNU-16 gastric cancer cells.
MedLine Citation:
PMID:  25407459     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
Paulina Grygielewicz; Barbara Dymek; Anna Bujak; Pawel Gunerka; Aleksandra Stanczak; Monika Lamparska-Przybysz; Maciej Wieczorek; Karolina Dzwonek; Daria Zdzalik
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-19
Journal Detail:
Title:  Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association     Volume:  -     ISSN:  1436-3291     ISO Abbreviation:  Gastric Cancer     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-11-19     Completed Date:  -     Revised Date:  2014-11-20    
Medline Journal Info:
Nlm Unique ID:  100886238     Medline TA:  Gastric Cancer     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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