Cargando…

Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model

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 ~15 to 25% of human iCCA patients. Here, we established a new iCCA model by expressing activated forms of Notch1 (NICD) and K-...

Descripción completa

Detalles Bibliográficos
Autores principales: Dong, Mingjie, Liu, Xianqiong, Evert, Katja, Utpatel, Kirsten, Peters, Michele, Zhang, Shanshan, Xu, Zhong, Che, Li, Cigliano, Antonio, Ribback, Silvia, Dombrowski, Frank, Cossu, Antonio, Gordan, John, Calvisi, Diego F., Evert, Matthias, Liu, Yan, Chen, Xin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833851/
https://www.ncbi.nlm.nih.gov/pubmed/29348467
http://dx.doi.org/10.1038/s41419-017-0183-4
_version_ 1783303551849594880
author Dong, Mingjie
Liu, Xianqiong
Evert, Katja
Utpatel, Kirsten
Peters, Michele
Zhang, Shanshan
Xu, Zhong
Che, Li
Cigliano, Antonio
Ribback, Silvia
Dombrowski, Frank
Cossu, Antonio
Gordan, John
Calvisi, Diego F.
Evert, Matthias
Liu, Yan
Chen, Xin
author_facet Dong, Mingjie
Liu, Xianqiong
Evert, Katja
Utpatel, Kirsten
Peters, Michele
Zhang, Shanshan
Xu, Zhong
Che, Li
Cigliano, Antonio
Ribback, Silvia
Dombrowski, Frank
Cossu, Antonio
Gordan, John
Calvisi, Diego F.
Evert, Matthias
Liu, Yan
Chen, Xin
author_sort Dong, Mingjie
collection PubMed
description 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 ~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.
format Online
Article
Text
id pubmed-5833851
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-58338512018-03-06 Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model Dong, Mingjie Liu, Xianqiong Evert, Katja Utpatel, Kirsten Peters, Michele Zhang, Shanshan Xu, Zhong Che, Li Cigliano, Antonio Ribback, Silvia Dombrowski, Frank Cossu, Antonio Gordan, John Calvisi, Diego F. Evert, Matthias Liu, Yan Chen, Xin Cell Death Dis Article 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 ~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. Nature Publishing Group UK 2018-01-18 /pmc/articles/PMC5833851/ /pubmed/29348467 http://dx.doi.org/10.1038/s41419-017-0183-4 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Dong, Mingjie
Liu, Xianqiong
Evert, Katja
Utpatel, Kirsten
Peters, Michele
Zhang, Shanshan
Xu, Zhong
Che, Li
Cigliano, Antonio
Ribback, Silvia
Dombrowski, Frank
Cossu, Antonio
Gordan, John
Calvisi, Diego F.
Evert, Matthias
Liu, Yan
Chen, Xin
Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title_full Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title_fullStr Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title_full_unstemmed Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title_short Efficacy of MEK inhibition in a K-Ras-driven cholangiocarcinoma preclinical model
title_sort efficacy of mek inhibition in a k-ras-driven cholangiocarcinoma preclinical model
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833851/
https://www.ncbi.nlm.nih.gov/pubmed/29348467
http://dx.doi.org/10.1038/s41419-017-0183-4
work_keys_str_mv AT dongmingjie efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT liuxianqiong efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT evertkatja efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT utpatelkirsten efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT petersmichele efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT zhangshanshan efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT xuzhong efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT cheli efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT ciglianoantonio efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT ribbacksilvia efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT dombrowskifrank efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT cossuantonio efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT gordanjohn efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT calvisidiegof efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT evertmatthias efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT liuyan efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel
AT chenxin efficacyofmekinhibitioninakrasdrivencholangiocarcinomapreclinicalmodel