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

doi:10.3390/ijms19103164

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

Department of Internal Medicine

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16 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 language	English
Article number	3164
Journal	International journal of molecular sciences
Volume	19
Issue number	10
DOIs	https://doi.org/10.3390/ijms19103164
Publication status	Published - 2018 Oct 15

Bibliographical note

Funding Information:
This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Funding Information:
Funding: This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation.

Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.

All Science Journal Classification (ASJC) codes

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

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10.3390/ijms19103164

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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), Article 3164. https://doi.org/10.3390/ijms19103164

@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 Rha, {Sun Young}",

note = "Funding Information: This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Funding Information: Funding: This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Publisher Copyright: {\textcopyright} 2018 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2018",

month = oct,

day = "15",

doi = "10.3390/ijms19103164",

language = "English",

volume = "19",

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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, Sun Young

N1 - Funding Information: This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Funding Information: Funding: This research was supported by grants from the National Cancer Center, Republic of Korea (NCC-1810861-1). This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education (NRF-2016R1D1A1B03932800). The funders had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. Publisher Copyright: © 2018 by the authors. Licensee MDPI, Basel, Switzerland.

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

Abstract

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