Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Guangdong Province Key Laboratory of Bioengineering Medicine, Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, National Engineering Research Center of Genetic Medicine, Ji'nan University, Guangzhou, 510632, China.
The First Affiliated Hospital, Ji'nan University, Guangzhou, 510630, China.
J Exp Clin Cancer Res. 2023 Apr 22;42(1):96. doi: 10.1186/s13046-023-02659-4.
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.
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.
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.
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.
肝细胞癌（HCC）是全球最常见和最致命的癌症之一，但目前的治疗选择仍然有限，并会导致严重的危及生命的副作用。异常的 FGFR4 信号已被验证为 HCC 的致癌驱动因素，而 EZH2 是 PRC2 复合物的催化亚基，是许多肿瘤（包括 HCC）获得性耐药的潜在因素。然而，这两个致癌因素之间的功能关系，特别是它们对 HCC 治疗的意义，尚不清楚。在这项研究中，我们系统地评估了针对 FGFR4 和 EZH2 的联合治疗 HCC 的可行性。
对来自癌症基因组图谱（TCGA）的肝细胞癌（LIHC）患者的 RNA 测序数据进行分析，以确定 FGFR4 和 EZH2 的表达及其与预后的相互作用。此外，用 FGFR4 抑制剂（Roblitinib）和/或 EZH2 抑制剂（CPI-169）处理 HCC 细胞系、斑马鱼/小鼠 HCC 异种移植和斑马鱼 HCC 原发性肿瘤，并进行细胞增殖、活力、凋亡和肿瘤生长分析，以评估体内外联合治疗 HCC 的可行性。此外，进行 RNA-Seq 并结合 ChIP-Seq 数据分析，以研究 Roblitinib 和 CPI-169 联合治疗的关键机制。
EZH2 通过非经典 NF-kB 信号在 FGFR4 抑制剂治疗后积累，升高的 EZH2 水平导致 HCC 对 Roblitinib（FGFR4 抑制剂）产生拮抗作用。值得注意的是，EZH2 的敲低使 HCC 细胞对 Roblitinib 敏感，而 Roblitinib 和 CPI-169（EZH2 抑制剂）的联合治疗在体外协同诱导 HCC 细胞凋亡，并在体内抑制斑马鱼/小鼠 HCC 异种移植和斑马鱼 HCC 原发性肿瘤的发展。此外，Roblitinib 和 CPI-169 通过抑制 YAP 信号协同抑制 HCC 的发展。
总之，我们的研究强调了 FGFR4 和 EZH2 抑制剂联合治疗的潜力，为 HCC 临床治疗策略的进一步发展提供了新的参考。
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