In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 11, No. 1 ( 2021-03-05)
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 FGF19 high (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 low (n = 105) patients, there were no significant differences between FGF19 high (n = 21) and FGF19 low (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.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-021-84117-9
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2021
detail.hit.zdb_id:
2615211-3
