Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition

Abstract

A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one third of all HCC in clinical series. S2 cells express E-cadherin, and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p<0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p<0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help identify those patients who are most likely to benefit from inhibition of this pathway.

Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models

“…Increasing evidence suggests that activation of FGF signaling pathways in HCC contributes to its malignancy . Therefore, we examined the antiproliferative activity of lenvatinib against nine HCC cell lines, and we showed that lenvatinib has inhibitory activity against HCC cell lines with activated FGF signaling pathways ; this proliferation inhibition was accompanied by suppressed FRS2 phosphorylation (Figs and ).…”

“…Activation of the FGF signaling pathways is associated with HCC progression, and proliferation of subsets of HCC is dependent on FGF signaling pathways . Because lenvatinib inhibits FGFRs, we first examined the antiproliferative activity of lenvatinib against nine HCC cell lines in vitro.…”

Identifying significant pathways of hepatitis B virus-related hepatocellular carcinoma based on crosstalk and network pathways

“…It was reported that FGFRs are presented on endothelial cells, and provide critical signaling pathways for HCC metastasis (Presta et al, 2005;Huynh et al, 2008). Schmidt et al (2016) revealed that the classification system may help identify HCC patients who are most likely to benefit FGFR inhibition. Furthermore, combined FGFR/mTOR treatment showed significant inhibitory effects on signaling and motility in HCC (Scheller et al, 2015).…”

Fibroblast Growth Factor 15/19 in Hepatocarcinogenesis

“…One early study showed that non-specific FGFR inhibitors quelled HCC cell growth and induced apoptosis [55] . It was later found that non-specific FGFR inhibitory compounds were particularly effective in HCC cells expressing FGFR4 and FGF19 [61] . Selective FGFR4 inhibitors have also been developed.…”

“…Its stimulation either by treatment with FGF19 or overexpression of FGFR4, and its inhibition by knocking down FGF19, FGFR4 or KLB, or by the overexpression of dominant-negative FGFR4 variants, has been shown to impact on HCC cell proliferation, survival, epithelial-mesenchymal transition (EMT), migration and invasion [33,37,38,49,50,55,58,60,61] . Interestingly, FGF19 may amplify its biological effects on HCC [62] and the EGFR ligand amphiregulin (AREG) in HCC cells, and that the growth-stimulating effects of FGF19 were mediated in part by autocrine AREG production [33] .…”