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The impact of FGF19/FGFR4 signaling inhibition in antitumor activity of multi-kinase inhibitors in hepatocellular carcinoma.
- Source :
-
Scientific reports [Sci Rep] 2021 Mar 05; Vol. 11 (1), pp. 5303. Date of Electronic Publication: 2021 Mar 05. - Publication Year :
- 2021
-
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 <superscript>high</superscript> (n = 68) patients treated using sorafenib exhibited a significantly shorter progression-free survival and overall survival than FGF19 <superscript>low</superscript> (n = 105) patients, there were no significant differences between FGF19 <superscript>high</superscript> (n = 21) and FGF19 <superscript>low</superscript> (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.
- Subjects :
- Animals
Cell Line, Tumor
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Phenylurea Compounds pharmacology
Quinolines pharmacology
Sorafenib pharmacology
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular drug therapy
Fibroblast Growth Factors metabolism
Liver Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Receptor, Fibroblast Growth Factor, Type 4 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 33674622
- Full Text :
- https://doi.org/10.1038/s41598-021-84117-9