Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Clin Cancer Res. 2021 Feb 15;27(4):1150-1161. doi: 10.1158/1078-0432.CCR-20-3382. Epub 2020 Dec 7.
Hepatocellular carcinoma (HCC) is characterized by high intertumor heterogeneity of genetic drivers. Two multitarget tyrosine kinase inhibitors (TKI), lenvatinib and sorafenib, are used as standard-of-care chemotherapeutics in patients with advanced HCC, but a stratification strategy has not been established because of a lack of efficacious biomarkers. Therefore, we sought biomarkers that indicate lenvatinib-susceptible HCC.
We performed genetic screening of HCC driver genes involved in TKI susceptibility using a novel HCC mouse model in which tumor diversity of genetic drivers was recapitulated. A biomarker candidate was evaluated in human HCC cell lines. Secreted proteins from HCC cells were then screened using mass spectrometry. Serum and tumor levels of the biomarker candidates were analyzed for their association and prediction of overall survival in patients with HCC.
We found that lenvatinib selectively eliminated FGF19-expressing tumors, whereas sorafenib eliminated MET- and NRAS-expressing tumors. FGF19 levels and lenvatinib susceptibility were correlated in HCC cell lines, and FGF19 inhibition eliminated lenvatinib susceptibility. Lenvatinib-resistant HCC cell lines, generated by long-term exposure to lenvatinib, showed FGF19 downregulation but were resensitized to lenvatinib by FGF19 reexpression. Thus, FGF19 is a tumor biomarker of lenvatinib-susceptible HCC. Proteome and secretome analyses identified ST6GAL1 as a tumor-derived secreted protein positively regulated by FGF19 in HCC cells. Serum ST6GAL1 levels were positively correlated with tumor FGF19 expression in patients with surgically resected HCC. Among patients with serum ST6GAL1-high HCC who underwent TKI therapy, lenvatinib therapy showed significantly better survival than sorafenib.
Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.
肝细胞癌 (HCC) 的特征是遗传驱动因素的肿瘤内异质性高。两种多靶点酪氨酸激酶抑制剂（TKI），仑伐替尼和索拉非尼，被用作晚期 HCC 患者的标准治疗化疗药物，但由于缺乏有效的生物标志物，尚未建立分层策略。因此，我们寻求表明仑伐替尼敏感的 HCC 的生物标志物。
我们使用一种新型 HCC 小鼠模型，该模型重现了遗传驱动因素的肿瘤多样性，对涉及 TKI 敏感性的 HCC 驱动基因进行了遗传筛选。在人 HCC 细胞系中评估了候选生物标志物。然后使用质谱法筛选 HCC 细胞分泌的蛋白质。分析了候选生物标志物的血清和肿瘤水平，以评估其与 HCC 患者总生存期的关联和预测。
我们发现仑伐替尼选择性消除 FGF19 表达的肿瘤，而索拉非尼消除 MET 和 NRAS 表达的肿瘤。FGF19 水平和仑伐替尼敏感性在 HCC 细胞系中相关，FGF19 抑制消除了仑伐替尼敏感性。通过长期暴露于仑伐替尼产生的仑伐替尼耐药 HCC 细胞系显示 FGF19 下调，但通过 FGF19 重新表达对仑伐替尼重新敏感。因此，FGF19 是仑伐替尼敏感 HCC 的肿瘤标志物。蛋白质组和分泌组分析确定 ST6GAL1 是一种肿瘤衍生的分泌蛋白，在 HCC 细胞中受 FGF19 正向调节。手术切除 HCC 患者的血清 ST6GAL1 水平与肿瘤 FGF19 表达呈正相关。在接受 TKI 治疗的血清 ST6GAL1 高 HCC 患者中，仑伐替尼治疗的生存情况明显优于索拉非尼。
血清 ST6GAL 可能是一种新的生物标志物，可识别仑伐替尼敏感的 FGF19 驱动 HCC。
