The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma

Chen, Zhongguang; Liang, Lifan; Koral, Kelly; Zhang, Qian; Zhao, Lei; Lu, Songjian; Tao, Junyan

doi:10.1016/j.ajpath.2021.04.014

Cited by 19 publications

(15 citation statements)

References 100 publications

(104 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Canonical and endocrine FGF signaling have essential roles in liver development, response to injury, and tumorigenesis (Z. Chen, Jiang, et al, 2021; Itoh, Nakayama, & Konishi, 2016; Seitz & Hellerbrand, 2021; Y. Wang, Liu, et al, 2021).…”

Section: Selected Topics In Genetics Development Regeneration and Dis...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

View full text Add to dashboard Cite

The fibroblast growth factor (FGF) family is composed of 18 secreted signaling proteins consisting of canonical FGFs and endocrine FGFs that activate four receptor tyrosine kinases (FGFRs 1-4) and four intracellular proteins (intracellular FGFs or iFGFs) that primarily function to regulate the activity of voltagegated sodium channels and other molecules. The canonical FGFs, endocrine FGFs, and iFGFs have been reviewed extensively by us and others. In this review, we briefly summarize past reviews and then focus on new developments in the FGF field since our last review in 2015. Some of the highlights in the past 6 years include the use of optogenetic tools, viral vectors, and inducible transgenes to experimentally modulate FGF signaling, the clinical use of small molecule FGFR inhibitors, an expanded understanding of endocrine FGF signaling, functions for FGF signaling in stem cell pluripotency and differentiation, roles for FGF signaling in tissue homeostasis and regeneration, a continuing elaboration of mechanisms of FGF signaling in development, and an expanding appreciation of roles for FGF signaling in neuropsychiatric diseases.

show abstract

Section: Selected Topics In Genetics Development Regeneration and Dis...mentioning

confidence: 99%

New developments in the biology of fibroblast growth factors

Ornitz

Itoh

2022

WIREs Mechanisms of Disease

View full text Add to dashboard Cite

show abstract

“…FGFR4 itself harbors an intracellular tyrosine kinase domain and elicits tyrosine phosphorylation on FRS2 upon FGF15/19 binding. Tyrosine-phosphorylated FRS2 is allowed to bind to growth factor-bound protein 2 (GRB2) to activate downstream signaling cascades to induce phosphorylation of ERK1/2 [ 155 , 156 , 157 ], after which phosphorylated ERK1/2 promotes mitogenesis of hepatocytes to regenerate liver tissue under physiological conditions [ 158 , 159 , 160 ] and progress hepatocarcinoma [ 128 , 161 , 162 ], neck squamous cell carcinoma [ 163 ], and gallbladder carcinoma cells [ 164 ] under pathogenic conditions. To eliminate these potentially harmful side effects, FGF19 analogs lacking mitogenic activity have been developed for future medication based on the aforementioned fact that some FGF19 mutants elicit normal Cyp7a1 reduction in the liver, but do not induce mitogenesis.…”

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

View full text Add to dashboard Cite

Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

show abstract

“…Dysregulation of FGF19/FGFR4/βklotho-mediated signal transduction through the MAPK, PI3K/AKT/mTOR, JAK-STAT, NFκB, and Wnt/β-catenin pathways can result in uncontrolled cellular growth in preclinical models of HCC [ 6 , 8 , 28 ]. Whereas this oncogenic mechanism is highly relevant to hepatobiliary cancers, dysregulation of the FGF19/FGFR4/βklotho signaling axis has also been observed in other solid tumors [ 6 – 8 ].…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid Tumors

et al. 2023

View full text Add to dashboard Cite

Introduction Fibroblast growth factor receptor (FGFR)-4/FGF19 pathway dysregulation is implicated in hepatobiliary and other solid tumors. INCB062079, an oral, selective, FGFR4 inhibitor, inhibits growth in FGF19/FGFR4-driven liver cancer models. Methods This was a two-part, phase I study (NCT03144661) in previously treated patients with advanced solid tumors. The primary objective was to determine safety, tolerability, and maximum tolerated dose (MTD), while secondary objectives included pharmacokinetics, pharmacodynamics (plasma FGF19; bile acid salts/7α-hydroxy-4-cholesten-3-one [C4] levels), and preliminary efficacy. In Part 1, patients received INCB062079 starting at 10 mg once daily, with 3 + 3 dose escalation. Part 2 (dose expansion) was not conducted because of study termination. Results Twenty-three patients were treated (hepatobiliary, n = 11; ovarian, n = 9; other, n = 3). Among six patients receiving 15 mg twice daily, two patients had dose-limiting toxicities (DLTs; grade 3 diarrhea, grade 3 transaminitis). Both had high pretreatment C4 concentrations, prompting a protocol amendment requiring pretreatment C4 concentrations < 40.9 ng/mL and concomitant prophylactic bile acid sequestrant treatment. No additional DLTs were reported at 10 and 15 mg twice daily; higher doses were not assessed. The most common toxicity was diarrhea (60.9%). INCB062079 exposure was dose-proportional; FGF19 and bile acid/C4 concentrations increased with exposure. One partial response was achieved (15 mg twice daily; ovarian cancer; FGF/FGFR status unknown; duration of response, 7.5 months); two patients had stable disease. Conclusions With C4 cut-off and prophylactic bile acid sequestrant implementation, INCB062079 demonstrated a manageable safety profile and evidence of target inhibition. In view of the rarity of FGF19/FGFR4 alterations and slow patient accrual, the study was terminated before establishing an MTD. Supplementary Information The online version contains supplementary material available at 10.1007/s11523-023-00948-8.

show abstract

The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma

Cited by 19 publications

References 100 publications

New developments in the biology of fibroblast growth factors

New developments in the biology of fibroblast growth factors

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

First-in-Human Study of INCB062079, a Fibroblast Growth Factor Receptor 4 Inhibitor, in Patients with Advanced Solid Tumors

Contact Info

Product

Resources

About