ST6GAL1 Is a Novel Serum Biomarker for Lenvatinib-Susceptible FGF19-Driven Hepatocellular Carcinoma
Autor: | Takahiro Kodama, Yuta Myojin, Daisuke Motooka, Yu Sato, Ayumu Taguchi, Ryotaro Sakamori, Kazuki Maesaka, Satoshi Tanaka, Tetsuo Takehara, Kazuyoshi Ohkawa, Hayato Hikita, Tomohide Tatsumi, Yoshito Hayashi, Hidetoshi Eguchi, Yuichi Abe, Eiji Mita |
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Rok vydání: | 2021 |
Předmět: |
Male
0301 basic medicine Cancer Research Mice chemistry.chemical_compound 0302 clinical medicine Aged 80 and over Liver Neoplasms Middle Aged Sorafenib Gene Expression Regulation Neoplastic Oncology 030220 oncology & carcinogenesis Hepatocellular carcinoma Quinolines Biomarker (medicine) Female Lenvatinib Tyrosine kinase medicine.drug Carcinoma Hepatocellular Down-Regulation Disease-Free Survival 03 medical and health sciences Downregulation and upregulation Antigens CD Cell Line Tumor Biomarkers Tumor medicine Animals Humans Protein Kinase Inhibitors neoplasms Aged business.industry Phenylurea Compounds FGF19 medicine.disease Sialyltransferases digestive system diseases Fibroblast Growth Factors 030104 developmental biology chemistry Drug Resistance Neoplasm Cell culture Cancer research Neoplasm Recurrence Local business Follow-Up Studies |
Zdroj: | Clinical Cancer Research. 27:1150-1161 |
ISSN: | 1557-3265 1078-0432 |
Popis: | 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. |
Databáze: | OpenAIRE |
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