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
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
Externí odkaz: