Z Gastroenterol 2019; 57(01): e72
DOI: 10.1055/s-0038-1677238
4. Tumors
Georg Thieme Verlag KG Stuttgart · New York

MEK inhibition suppresses cholangiocarcinoma growth by restraining tumor cell proliferation and modulating tumor microenvironment

K Utpatel
1   Institute of Pathology, University of Regensburg, Regensburg, Germany
,
P Wang
2   Beijing Advanced Innovatio Center for Food Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
X Song
2   Beijing Advanced Innovatio Center for Food Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
R Shang
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
5   Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China
,
M Xu
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
4   Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi'an, China
,
L Che
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
J Gordan
6   Department of Medicine, University of California, San Francisco, CA, USA
,
X Hu
2   Beijing Advanced Innovatio Center for Food Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
,
X Chen
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
M Evert
1   Institute of Pathology, University of Regensburg, Regensburg, Germany
,
DF Calvisi
1   Institute of Pathology, University of Regensburg, Regensburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background:

Cholangiocarcinoma (CCA) is an aggressive form of liver malignancy with limited therapeutic options. PD901 is a MEK inhibitor, showing therapeutic efficacy in CCA harboring oncogenic mutations of the K-Ras gene. However, most of CCA exhibit no K-Ras mutations. Thus, it is crucial to determine whether MEK inhibitors also function to inhibit the growth of CCA with wildtype K-Ras alleles.

Methods:

In this study, we investigated the therapeutic potential of MEK inhibitor, PD901, alone or in combination of pan-mTOR inhibitor, MLN0128, for the treatment of K-Ras wildtype CCA in vitro and in vivo using human CCA cell lines and AKT/YapS127A CCA mouse model, respectively.

Results:

In vitro, treatment with MEK inhibitor strongly inhibited CCA cell proliferation, and combined MEK and mTOR inhibitors led to increased growth inhibition. In AKT/YapS127A murine CCA model, we found treatment of PD901 treatment alone resulted in tumor regression whereas combined PD901 and MLN0128 treatment did not lead to additional tumor burden reduction. Mechanistically, PD901 efficiently inhibited ERK activation in vitro and in vivo, leading to strong inhibiting of tumor cell cycle progression. Intriguingly, we found that PD901 but not MLN0128 treatment resulted in the changes of vasculature as well as cancer-associated fibroblasts in AKT/YapS127A murine CCA model.

Conclusion:

In summary, our studies demonstrate that MEK inhibitors could be effective for the treatment of K-Ras wildtype CCA via inhibiting tumor cell proliferation and modulating tumor microenvironment.