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, SunYoung Rha

Research output: Contribution to journalArticle

3 Citations (Scopus)

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

Fingerprint

Fibroblast Growth Factor Receptors
fibroblasts
Fibroblasts
Paclitaxel
inhibitors
cancer
Cells
Carcinoma
Administrative data processing
Chemotherapy
Flow cytometry
Cell death
RNA
Tumors
Platinum
Assays
Epithelial-Mesenchymal Transition
Proteins
Cell Movement
ribose

All Science Journal Classification (ASJC) codes

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

Cite this

Kim, Se Hyun ; Ryu, Haram ; Ock, Chan Young ; Suh, Koung Jin ; Lee, Ji Yun ; Kim, Ji Won ; Lee, Jeong Ok ; Kim, Jin Won ; Kim, Yu Jung ; Lee, Keun Wook ; Bang, Soo Mee ; Kim, Jee Hyun ; Lee, Jong Seok ; Ahn, Joong Bae ; Kim, Kui Jin ; Rha, SunYoung. / BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression. In: International journal of molecular sciences. 2018 ; Vol. 19, No. 10.
@article{9600c963b5524ab08e6666a87716e7d8,
title = "BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression",
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.",
author = "Kim, {Se Hyun} and Haram Ryu and Ock, {Chan Young} and Suh, {Koung Jin} and Lee, {Ji Yun} and Kim, {Ji Won} and Lee, {Jeong Ok} and Kim, {Jin Won} and Kim, {Yu Jung} and Lee, {Keun Wook} and Bang, {Soo Mee} and Kim, {Jee Hyun} and Lee, {Jong Seok} and Ahn, {Joong Bae} and Kim, {Kui Jin} and SunYoung Rha",
year = "2018",
month = "10",
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doi = "10.3390/ijms19103164",
language = "English",
volume = "19",
journal = "International Journal of Molecular Sciences",
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Kim, SH, Ryu, H, Ock, CY, Suh, KJ, Lee, JY, Kim, JW, Lee, JO, Kim, JW, Kim, YJ, Lee, KW, Bang, SM, Kim, JH, Lee, JS, Ahn, JB, Kim, KJ & Rha, S 2018, 'BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression', International journal of molecular sciences, vol. 19, no. 10, 3164. https://doi.org/10.3390/ijms19103164

BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression. / Kim, Se Hyun; Ryu, Haram; Ock, Chan Young; Suh, Koung Jin; Lee, Ji Yun; Kim, Ji Won; Lee, Jeong Ok; Kim, Jin Won; Kim, Yu Jung; Lee, Keun Wook; Bang, Soo Mee; Kim, Jee Hyun; Lee, Jong Seok; Ahn, Joong Bae; Kim, Kui Jin; Rha, SunYoung.

In: International journal of molecular sciences, Vol. 19, No. 10, 3164, 15.10.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - BGJ398, a pan-FGFR inhibitor, overcomes paclitaxel resistance in urothelial carcinoma with FGFR1 overexpression

AU - Kim, Se Hyun

AU - Ryu, Haram

AU - Ock, Chan Young

AU - Suh, Koung Jin

AU - Lee, Ji Yun

AU - Kim, Ji Won

AU - Lee, Jeong Ok

AU - Kim, Jin Won

AU - Kim, Yu Jung

AU - Lee, Keun Wook

AU - Bang, Soo Mee

AU - Kim, Jee Hyun

AU - Lee, Jong Seok

AU - Ahn, Joong Bae

AU - Kim, Kui Jin

AU - Rha, SunYoung

PY - 2018/10/15

Y1 - 2018/10/15

N2 - 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.

AB - 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.

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U2 - 10.3390/ijms19103164

DO - 10.3390/ijms19103164

M3 - Article

VL - 19

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

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