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FGFR4 and EZH2 inhibitors synergistically induce hepatocellular carcinoma apoptosis via repressing YAP signaling

Background: Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide, but current treatment options remain limited and cause serious life-threatening side effects. Aberrant FGFR4 signaling has been validated as an oncogenic driver of HCC, and EZH2, the catalytic subunit of the PRC2 complex, is a potential factor that contributes to acquired drug resistance in many tumors, including HCC. However, the functional relationship between these two carcinogenic factors, especially their significance for HCC treatment, remains unclear. In this study, we systematically evaluated the feasibility of a combination therapy targeting FGFR4 and EZH2 for HCC.

Methods: RNA sequencing data of patients with Liver hepatocellular carcinoma (LIHC) from The Cancer Genome Atlas (TCGA) were analyzed to determine FGFR4 and EZH2 expression and their interaction with prognosis. Moreover, the HCC cell lines, zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors were treated with FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) and then subjected to cell proliferation, viability, apoptosis, and tumor growth analyses to evaluate the feasibility of combination therapy for HCC both in vitro and in vivo. Furthermore, RNA-Seq was performed in combination with ChIP-Seq data analysis to investigate the critical mechanism underlying the combination treatment with Roblitinib and CPI-169.

Results: EZH2 accumulated through the non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment, and the elevated EZH2 levels led to the antagonism of HCC against Roblitinib (FGFR4 inhibitor). Notably, knockdown of EZH2 sensitized HCC cells to Roblitinib, while the combination treatment of Roblitinib and CPI-169 (EZH2 inhibitor) synergistically induced the HCC cell apoptosis in vitro and suppressed the zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors development in vivo. Moreover, Roblitinib and CPI-169 synergistically inhibited HCC development via repressing YAP signaling.

Conclusions: Collectively, our study highlighted the potential of the therapeutic combination of FGFR4 and EZH2 inhibitors, which would provide new references for the further development of clinical treatment strategies for HCC.

 

Comments:

In this study, the researchers aimed to investigate the feasibility of a combination therapy targeting FGFR4 and EZH2 for hepatocellular carcinoma (HCC). They analyzed RNA sequencing data from HCC patients in the TCGA database to assess the expression of FGFR4 and EZH2 and their association with prognosis. Additionally, they conducted in vitro and in vivo experiments using HCC cell lines, zebrafish/mouse HCC xenografts, and zebrafish HCC primary tumors to evaluate the effects of FGFR4 inhibitor (Roblitinib) and/or EZH2 inhibitor (CPI-169) treatment on cell proliferation, viability, apoptosis, and tumor growth. They also performed RNA sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) analyses to elucidate the underlying mechanisms of the combination treatment.

The results of the study showed that EZH2 levels increased through non-canonical NF-kB signaling in response to FGFR4 inhibitor treatment. The elevated levels of EZH2 led to resistance against Roblitinib in HCC. However, knockdown of EZH2 sensitized HCC cells to Roblitinib treatment. Moreover, the combination treatment of Roblitinib and CPI-169 synergistically induced apoptosis in HCC cells in vitro and suppressed the development of zebrafish/mouse HCC xenografts and zebrafish HCC primary tumors in vivo. The researchers also found that the combination therapy repressed YAP signaling, contributing to the inhibition of HCC development.

In conclusion, this study demonstrated the potential of a therapeutic combination of FGFR4 and EZH2 inhibitors for HCC treatment. By targeting both FGFR4 and EZH2, the researchers observed enhanced therapeutic effects compared to individual inhibitor treatments. These findings provide valuable insights for the development of new clinical treatment strategies for HCC.

Related Products

Cat.No. Product Name Information
S8548 Roblitinib (FGF401) Roblitinib (FGF401) is an FGFR4-selective inhibitor with an IC50 of 1.9 nM. It binds in a reversible covalent manner to the FGFR4 kinase domain and shows at least 1,000 fold selectivity against of panel of 65 kinases in biochemical assays.

Related Targets

FGFR