These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.<i>See related commentary by Subbiah and Pal, p. 1646</i>.<i>This article is highlighted in the In This Issue feature, p. 1631</i>.
FGFR4 is therefore a promising target for the treatment of HCC harboring aberrant FGF19-FGFR4 signaling, and several FGFR4 inhibitors have advanced to clinical trial.
FGF401 has remarkable antitumor activity in mice bearing HCC tumor xenografts and patient-derived xenograft models that are positive for FGF19, FGFR4, and KLB.
Many molecular alterations of the receptor and its ligands, specially FGF19, have been reported in several types of cancer, with special relevance in hepatocellular carcinoma.
Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefit and tumor regression in patients with HCC with aberrant FGF19 expression.
CONCLUSION: We defined a FGF19-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.
This study explored the potential of FGF19- and FGFR4-related biomarkers in predicting early tumour recurrence (ETR) and survival in patients with resectable hepatocellular carcinoma (HCC).
Finally, we investigated the biological function of SNHG16 in HCC and showed that SNHG16 promoted liver cancer cells proliferation via the SNHG16/miR-302a-3p/FGF19 axis.
Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.
Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism.
Here we present a novel and intriguing view on the putative possibility to target the FXR-FGF19 duo in order to offer a bona fide promising therapeutic approach to bile acid promoted hepatocarcinoma.
Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19.<i></i>.
Unlike FGF19, FGF15 did not induce hepatocellular carcinomas (HCC) in three mouse models of metabolic diseases (db/db, diet-induced obese, and multi-drug resistance 2 [Mdr2]-deficient mice), even at supra-pharmacological exposure levels.
Our findings show how FGF19 provides a cytoprotective role against ER stress by activating a FGFR4-GSK3β-Nrf2 signaling cascade, with implications for targeting this signaling node as a candidate therapeutic regimen for HCC management.<i></i>.
FGF19 is a promising therapeutic target for the metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma.
Collectively, these data reveal a key role for the IL-6/STAT3 axis in potentiating FGF19-driven HCC in mice, a finding which may have translational relevance in HCC pathogenesis.
As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.