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BGJ398, A Pan-FGFR Inhibitor, Overcomes Paclitaxel Resistance in Urothelial Carcinoma with FGFR1 Overexpression

Authors
 Se Hyun Kim  ;  Haram Ryu  ;  Chan-Young Ock  ;  Koung Jin Suh  ;  Ji Yun Lee  ;  Ji-Won Kim  ;  Jeong-Ok Lee  ;  Jin Won Kim  ;  Yu Jung Kim  ;  Keun-Wook Lee  ;  Soo-Mee Bang  ;  Jee Hyun Kim  ;  Jong Seok Lee  ;  Joong Bae Ahn  ;  Kui-Jin Kim  ;  Sun Young Rha 
Citation
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol.19(10) : 3164, 2018 
Journal Title
 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 
Issue Date
2018
Keywords
BGJ398 ; FGFR ; FGFR inhibitor ; combination therapy ; epithelial-to-mesenchymal transition ; paclitaxel ; urothelial carcinoma
Abstract
Paclitaxel (PTX) is commonly used to treat urothelial carcinoma (UC) after platinum-based chemotherapy has failed. However, single-agent taxane therapy is not sufficient to inhibit tumor progression and drug resistance in advanced UC. Epithelial-to-mesenchymal transition (EMT) induced by fibroblast growth factor receptor (FGFR)1 signaling has been proposed as a mechanism of PTX resistance, but it is unclear whether this can be overcome by FGFR1 inhibition. The present study investigated whether FGFR1 overexpression contributes to PTX resistance and whether FGFR inhibition can enhance PTX efficacy in UC. The effects of PTX combined with the FGFR inhibitor BGJ398 were evaluated in UC cell lines by flow cytometry; Western blot analysis; cell viability, migration, and colony forming assays; and RNA interference. PTX+BGJ398 induced cell cycle arrest and apoptosis in UC cells with mesenchymal characteristics was accompanied by downregulation of cyclin D1 protein and upregulation of gamma-histone 2A family member X and cleaved poly(ADP-ribose) polymerase. Additionally, PTX+BGJ398 synergistically suppressed UC cell migration and colony formation via regulation of EMT-associated factors, while FGFR1 knockdown enhanced the antitumor effect of PTX. These findings provide a basis for development of effective strategies for overcoming PTX resistance in UC through inhibition of FGFR1 signaling.
Files in This Item:
T201803995.pdf Download
DOI
10.3390/ijms19103164
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Ahn, Joong Bae(안중배) ORCID logo https://orcid.org/0000-0001-6787-1503
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/165428
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