Scientific Reports (Mar 2021)

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

  • 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

DOI
https://doi.org/10.1038/s41598-021-84117-9
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 12

Abstract

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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.