ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma

伦瓦提尼 肝细胞癌 FGF19型 内科学 医学 肿瘤科 肝细胞癌 生物标志物 癌症研究 生物 成纤维细胞生长因子 索拉非尼 受体 遗传学
作者
Yuta Myojin,Takahiro Kodama,Kazuki Maesaka,Daisuke Motooka,Yu Sato,Satoshi Tanaka,Yuichi Abe,Kazuyoshi Ohkawa,Eiji Mita,Yoshito Hayashi,Hayato Hikita,Ryotaro Sakamori,Tomohide Tatsumi,Ayumu Taguchi,Hidetoshi Eguchi,Tetsuo Takehara
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:27 (4): 1150-1161 被引量:59
标识
DOI:10.1158/1078-0432.ccr-20-3382
摘要

Abstract Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: Serum ST6GAL may be a novel biomarker that identifies lenvatinib-susceptible FGF19-driven HCC.
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