Dong, Mingjie and Liu, Xianqiong and Evert, Katja and Utpatel, Kirsten and Peters, Michele and Zhang, Shanshan and Xu, Zhong and Che, Li and Cigliano, Antonio and Ribback, Silvia and Dombrowski, Frank and Cossu, Antonio and Gordan, John and Calvisi, Diego F. and Evert, Matthias and Liu, Yan and Chen, Xin (2018) Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model. CELL DEATH & DISEASE, 9: 31. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a deadly malignancy with limited treatment options. Gain-of-function mutations in K-Ras is a very frequent alteration, occurring in similar to 15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-Ras (K-Ras(V12D)) in the mouse liver (K-Ras/NICD mice). Furthermore, we investigated the therapeutic potential of MEK inhibitors in vitro and in vivo using human CCA cell lines and K-Ras/NICD mice, respectively. Treatment with U0126, PD901, and Selumetinib MEK inhibitors triggered growth restraint in all CCA cell lines tested, with the most pronounced growth suppressive effects being observed in K-Ras mutant cells. Growth inhibition was due to reduction in proliferation and massive apoptosis. Furthermore, treatment of K-Ras/NICD tumor-bearing mice with PD901 resulted in stable disease. At the molecular level, PD901 efficiently inhibited ERK activation in K-Ras/NICD tumor cells, mainly leading to increased apoptosis. Altogether, our study demonstrates that K-Ras/NICD mice represent a novel and useful preclinical model to study K-Ras-driven iCCA development and the effectiveness of MEK inhibitors in counteracting this process. Our data support the usefulness of MEK inhibitors for the treatment of human iCCA.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BILIARY-TRACT; INTRAHEPATIC CHOLANGIOCARCINOMA; CANCER; LIVER; MICE; GENERATION; DISCOVERY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2020 08:40 |
| Last Modified: | 24 Mar 2020 08:40 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15191 |
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