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

Authors
  • Kanzaki, Hiroaki1
  • Chiba, Tetsuhiro1
  • Ao, Junjie1
  • Koroki, Keisuke1
  • Kanayama, Kengo1
  • Maruta, Susumu1
  • Maeda, Takahiro1
  • Kusakabe, Yuko1
  • Kobayashi, Kazufumi1
  • Kanogawa, Naoya1
  • Kiyono, Soichiro1
  • Nakamura, Masato1
  • Kondo, Takayuki1
  • Saito, Tomoko1
  • Nakagawa, Ryo1
  • Ogasawara, Sadahisa1
  • Suzuki, Eiichiro1
  • Ooka, Yoshihiko1
  • Muroyama, Ryosuke1
  • Nakamoto, Shingo1
  • And 11 more
  • 1 Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan , Chiba (Japan)
  • 2 Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan , Tokyo (Japan)
  • 3 Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan , Tokyo (Japan)
  • 4 Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan , Chiba (Japan)
  • 5 King’s College Hospital, London, UK , London (United Kingdom)
  • 6 The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan , Tokyo (Japan)
Type
Published Article
Journal
Scientific Reports
Publisher
Springer Nature
Publication Date
Mar 05, 2021
Volume
11
Issue
1
Identifiers
DOI: 10.1038/s41598-021-84117-9
Source
Springer Nature
License
Green

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.

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