Targeted inhibition of FGF19/FGFR cascade improves antitumor immunity and response rate in hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. Overexpression of broblast growth factor (FGF) receptors (FGFRs) signaling cascade has been shown to contribute to tumorigenesis, metastasis, and poor prognosis in HCC. Therefore, targeted inhibition of the FGF/FGFR cascade may represent a new treatment strategy for HCC patients. MethodsHCC patient-derived xenograft (PDX) models were implanted into either severe combined immunode cient (SCID) or CD34 + hu-NSG (humanized) mice and subsequently treated with vehicle, in gratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of in gratinib and FGF401.Tumor progressions, overall survival of mice, lung metastasis, and drug resistance were monitored, and samples collected at the end of the treatment cycle were subjected to Western blot analyses and immunohistochemistry. ResultsHCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and in gratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination in gratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination signi cantly increased the in ltration of B-cells, macrophages, CD8 + T-cells, and CD4 + T-cells associated with granzyme-B mediated apoptosis, delayed onset of resistance, and inhibited metastasis by potently inhibiting several critical signaling pathways involved in proliferation and metastasis. ConclusionsOur ndings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might bene t from a combination in gratinib/FGF401, thus supporting its evaluation in clinical trials.

A first-in-human phase 1/2 study of FGF401 and combination of FGF401 with spartalizumab in patients with hepatocellular carcinoma or biomarker-selected solid tumors

“…FGF401 is one of the promising reversible FGFR4 inhibitor, which may have improved effects over irreversible inhibitors [ 36 ]. In a preclinical study, FGF401 was studied in combination with FGFR1–3 inhibitor, infigratinib, and found that HCC patients with high expression of FGFR2/3 or FGF19/FGFR4 might benefit from the combination if evaluated further in the clinical studies [ 37 ].…”

A bile acid-related prognostic signature in hepatocellular carcinoma

“…FGF19 is a dietary-responsive endocrine hormone essential for enterohepatic circulation of BAs 13 . Abnormal expression of FGF19-FGFR4 has been shown to accelerate hepatocarcinogenesis and metastasis, while inhibition of the FGF19/FGFR pathway augments tumor-suppressive activity and improves the prognosis in patients with HCC 14 , 15 . In summary, the role of BAGs in hepatic carcinogenesis and prognosis is variable and worthy of further research.…”

Identification, Characterization and Functional Analysis of Fibroblast Growth Factors in Black Rockfish (Sebastes schlegelii)

“…The results showed that FGF genes were ubiquitously expressed in different tissues and developmental stages with divergent expressions, suggesting that FGFs are widely involved in various biological processes and perform multiple biological functions in S. schlegelii , as reported in mammals. For instance, FGF19 , was found to be specifically expressed in the liver of S. schlegelii , implying that it may be involved in liver physiological function, including glycogen metabolism [ 34 ], lipid metabolism [ 35 ], and immune response [ 36 ], as demonstrated in mammals. In zebrafish, FGF signaling has also been widely verified to play a key role in liver homeostasis regulation and specification [ 37 , 38 ].…”