The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma

Abstract FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signali...

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Autores principales: Hiroaki Kanzaki, Tetsuhiro Chiba, Junjie Ao, Keisuke Koroki, Kengo Kanayama, Susumu Maruta, Takahiro Maeda, Yuko Kusakabe, Kazufumi Kobayashi, Naoya Kanogawa, Soichiro Kiyono, Masato Nakamura, Takayuki Kondo, Tomoko Saito, Ryo Nakagawa, Sadahisa Ogasawara, Eiichiro Suzuki, Yoshihiko Ooka, Ryosuke Muroyama, Shingo Nakamoto, Shin Yasui, Akinobu Tawada, Makoto Arai, Tatsuo Kanda, Hitoshi Maruyama, Naoya Mimura, Jun Kato, Yoh Zen, Masayuki Ohtsuka, Atsushi Iwama, Naoya Kato
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Lenguaje:EN
Publicado: Nature Portfolio 2021
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spelling oai:doaj.org-article:291df543461344c18b5823f3f97cddec2021-12-02T11:35:58ZThe impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma10.1038/s41598-021-84117-92045-2322https://doaj.org/article/291df543461344c18b5823f3f97cddec2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84117-9https://doaj.org/toc/2045-2322Abstract FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.Hiroaki KanzakiTetsuhiro ChibaJunjie AoKeisuke KorokiKengo KanayamaSusumu MarutaTakahiro MaedaYuko KusakabeKazufumi KobayashiNaoya KanogawaSoichiro KiyonoMasato NakamuraTakayuki KondoTomoko SaitoRyo NakagawaSadahisa OgasawaraEiichiro SuzukiYoshihiko OokaRyosuke MuroyamaShingo NakamotoShin YasuiAkinobu TawadaMakoto AraiTatsuo KandaHitoshi MaruyamaNaoya MimuraJun KatoYoh ZenMasayuki OhtsukaAtsushi IwamaNaoya KatoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Hiroaki Kanzaki
Tetsuhiro Chiba
Junjie Ao
Keisuke Koroki
Kengo Kanayama
Susumu Maruta
Takahiro Maeda
Yuko Kusakabe
Kazufumi Kobayashi
Naoya Kanogawa
Soichiro Kiyono
Masato Nakamura
Takayuki Kondo
Tomoko Saito
Ryo Nakagawa
Sadahisa Ogasawara
Eiichiro Suzuki
Yoshihiko Ooka
Ryosuke Muroyama
Shingo Nakamoto
Shin Yasui
Akinobu Tawada
Makoto Arai
Tatsuo Kanda
Hitoshi Maruyama
Naoya Mimura
Jun Kato
Yoh Zen
Masayuki Ohtsuka
Atsushi Iwama
Naoya Kato
The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
description Abstract FGF19/FGFR4 autocrine signaling is one of the main targets for multi-kinase inhibitors (MKIs). However, the molecular mechanisms underlying FGF19/FGFR4 signaling in the antitumor effects to MKIs in hepatocellular carcinoma (HCC) remain unclear. In this study, the impact of FGFR4/ERK signaling inhibition on HCC following MKI treatment was analyzed in vitro and in vivo assays. Serum FGF19 in HCC patients treated using MKIs, such as sorafenib (n = 173) and lenvatinib (n = 40), was measured by enzyme-linked immunosorbent assay. Lenvatinib strongly inhibited the phosphorylation of FRS2 and ERK, the downstream signaling molecules of FGFR4, compared with sorafenib and regorafenib. Additional use of a selective FGFR4 inhibitor with sorafenib further suppressed FGFR4/ERK signaling and synergistically inhibited HCC cell growth in culture and xenograft subcutaneous tumors. Although serum FGF19high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19low (n = 105) patients, there were no significant differences between FGF19high (n = 21) and FGF19low (n = 19) patients treated using lenvatinib. In conclusion, robust inhibition of FGF19/FGFR4 is of importance for the exertion of antitumor effects of MKIs. Serum FGF19 levels may function as a predictive marker for drug response and survival in HCC patients treated using sorafenib.
format article
author Hiroaki Kanzaki
Tetsuhiro Chiba
Junjie Ao
Keisuke Koroki
Kengo Kanayama
Susumu Maruta
Takahiro Maeda
Yuko Kusakabe
Kazufumi Kobayashi
Naoya Kanogawa
Soichiro Kiyono
Masato Nakamura
Takayuki Kondo
Tomoko Saito
Ryo Nakagawa
Sadahisa Ogasawara
Eiichiro Suzuki
Yoshihiko Ooka
Ryosuke Muroyama
Shingo Nakamoto
Shin Yasui
Akinobu Tawada
Makoto Arai
Tatsuo Kanda
Hitoshi Maruyama
Naoya Mimura
Jun Kato
Yoh Zen
Masayuki Ohtsuka
Atsushi Iwama
Naoya Kato
author_facet Hiroaki Kanzaki
Tetsuhiro Chiba
Junjie Ao
Keisuke Koroki
Kengo Kanayama
Susumu Maruta
Takahiro Maeda
Yuko Kusakabe
Kazufumi Kobayashi
Naoya Kanogawa
Soichiro Kiyono
Masato Nakamura
Takayuki Kondo
Tomoko Saito
Ryo Nakagawa
Sadahisa Ogasawara
Eiichiro Suzuki
Yoshihiko Ooka
Ryosuke Muroyama
Shingo Nakamoto
Shin Yasui
Akinobu Tawada
Makoto Arai
Tatsuo Kanda
Hitoshi Maruyama
Naoya Mimura
Jun Kato
Yoh Zen
Masayuki Ohtsuka
Atsushi Iwama
Naoya Kato
author_sort Hiroaki Kanzaki
title The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
title_short The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
title_full The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
title_fullStr The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
title_full_unstemmed The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
title_sort impact of fgf19/fgfr4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma
publisher Nature Portfolio
publishDate 2021
url https://doaj.org/article/291df543461344c18b5823f3f97cddec
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