Background

Hepatocellular carcinoma (HCC) is the most common liver cancer globally, claiming nearly 1 million lives each year. The overexpression of fibroblast 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.

Methods

HCC patient-derived xenograft (PDX) models were implanted into either severe combined immunodeficient (SCID) or CD34+hu-NSG (humanized) mice and subsequently treated with vehicle, infigratinib (FGFR1-3 inhibitor), FGF401 (FGFR4 inhibitor), or the combination of infigratinib 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.

Results

HCC PDX models expressing high levels of FGF19/FGFR4 or FGFR2/3 showed favorable initial treatment response to FGF401 and infigratinib, respectively. However, progressive disease due to acquired resistance was observed. Combination infigratinib/FGF401 augmented the antitumor activity, response rate, and overall survival of mice. This combination significantly increased the infiltration 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.

Conclusions

Our findings suggest that HCC patients with high FGFR2/3 or FGF19/FGFR4 expressing tumors might benefit from a combination infigratinib/FGF401; thus, supporting its evaluation in clinical trials.

中文翻译：

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靶向抑制 FGF19/FGFR 级联反应可提高肝细胞癌的抗肿瘤免疫和反应率

背景

肝细胞癌 (HCC) 是全球最常见的肝癌，每年夺去近 100 万人的生命。已显示成纤维细胞生长因子 (FGF) 受体 (FGFR) 信号级联的过度表达有助于 HCC 的肿瘤发生、转移和不良预后。因此，靶向抑制 FGF/FGFR 级联可能代表 HCC 患者的新治疗策略。

方法

HCC 患者来源的异种移植 (PDX) 模型被植入严重联合免疫缺陷 (SCID) 或 CD34+hu-NSG（人源化）小鼠，随后用载体、infigratinib（FGFR1-3 抑制剂）、FGF401（FGFR4 抑制剂）或infigratinib 和 FGF401 的组合。监测肿瘤进展、小鼠的总体存活率、肺转移和耐药性，并对治疗周期结束时收集的样本进行蛋白质印迹分析和免疫组织化学。

结果

表达高水平 FGF19/FGFR4 或 FGFR2/3 的 HCC PDX 模型分别对 FGF401 和 infigratinib 显示出良好的初始治疗反应。然而，观察到由于获得性抗性引起的进行性疾病。infigratinib/FGF401 组合增强了小鼠的抗肿瘤活性、反应率和总体存活率。这种组合显着增加了 B 细胞、巨噬细胞、CD8+ T 细胞和 CD4+ T 细胞的浸润，这些浸润与颗粒酶 B 介导的细胞凋亡相关，延迟了耐药性的发生，并通过有效抑制参与增殖和转移的几个关键信号通路来抑制转移。

结论

我们的研究结果表明，具有高 FGFR2/3 或 FGF19/FGFR4 表达肿瘤的 HCC 患者可能受益于 infigratinib/FGF401 的组合；因此，支持其在临床试验中的评估。