BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression

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

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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.

Original languageEnglish
Article number3164
JournalInternational journal of molecular sciences
Volume19
Issue number10
DOIs
Publication statusPublished - 2018 Oct 15

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All Science Journal Classification (ASJC) codes

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Kim, S. H., Ryu, H., Ock, C. Y., Suh, K. J., Lee, J. Y., Kim, J. W., Lee, J. O., Kim, J. W., Kim, Y. J., Lee, K. W., Bang, S. M., Kim, J. H., Lee, J. S., Ahn, J. B., Kim, K. J., & Rha, S. Y. (2018). BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression. International journal of molecular sciences, 19(10), [3164]. https://doi.org/10.3390/ijms19103164