Ponatinib inhibits growth of patient-derived xenograft of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein in nude mice.
10.12122/j.issn.1673-4254.2020.10.10
- Author:
Tianyu WU
1
;
Xiaoqing JIANG
2
;
Bin XU
1
;
Yu WANG
1
Author Information
1. Department of Hepatobiliary Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
2. Surgical Intensive Care Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
- Publication Type:Journal Article
- Keywords:
FGFR2;
cisplatin;
gemcitabine;
intrahepatic cholangiocarcinoma;
ponatinib
- MeSH:
Animals;
Bile Duct Neoplasms/genetics*;
Cell Line, Tumor;
Cell Proliferation;
Cholangiocarcinoma/genetics*;
Cytoskeletal Proteins;
Heterografts;
Humans;
Imidazoles;
Mice;
Mice, Inbred NOD;
Mice, Nude;
Mice, SCID;
Pyridazines;
Receptor, Fibroblast Growth Factor, Type 2;
Xenograft Model Antitumor Assays
- From:
Journal of Southern Medical University
2020;40(10):1448-1456
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To investigate the antitumor effect of ponatinib on the growth of cholangiocarcinoma xenograft derived from a clinical patient in a mouse model expressing FGFR2-CCDC6 fusion protein.
METHODS:Lung metastatic tumor tissue was collected from a patient with advanced intrahepatic cholangiocarcinoma and implanted subcutaneously a NOD/SCID/ Il2rg-knockout (NSG) mouse. The tumor tissues were harvested and transplanted in nude mice to establish mouse models bearing patient-derived xenograft (PDX) of cholangiocarcinoma expressing FGFR2-CCDC6 fusion protein. The PDX mouse models were divided into 4 groups for treatment with citrate buffer (control group), intragastric administration of 20 mg/kg ponatinib dissolved in citrate buffer (ponatinib group), weekly intraperitoneal injections of 50 mg/kg gemcitabine and 2.5 mg/ kg cisplatin (gemcitabine group), or ponatinib combined with gemcitabine and cisplatin at the same doses (10 mice in each group, and 9 mice were evaluated in ponatinib group). The expressions of p-FGFR, p-FRS2, p-AKT, p-ERK, CD31, and Ki-67 in the xenografts were evaluated with immunohistochemistry, and cell apoptosis was analyzed with cleaved caspase-3 (CC3) staining and TUNEL staining. Western blotting was used to detect the expressions of FGFR2, p-FGFR, AKT, p-AKT, ERK, p-ERK, FRS2 and p-FRS2 in the tumor tissues.
RESULTS:Compared with those in the control group, the mice in ponatinib group showed a significantly reduced tumor volume (
CONCLUSIONS:Ponatinib can regulate FGFR signaling to inhibit the proliferation and induce apoptosis of tumor cells in mice bearing patient-derived cholangiocarcinoma xenograft with FGFR2 fusion. FGFR inhibitor can serve as a treatment option for patients with cholangiocarcinoma with FGFR2 fusion.
