Wang, Pan and Song, Xinhua and Utpatel, Kirsten and Shang, Runze and Yang, Yoon Mee and Xu, Meng and Zhang, Jie and Che, Li and Gordan, John and Cigliano, Antonio and Seki, Ekihiro and Evert, Matthias and Calvisi, Diego F. and Hu, Xiaosong and Chen, Xin (2019) MEK inhibition suppresses K-Ras wild-type cholangiocarcinoma in vitro and in vivo via inhibiting cell proliferation and modulating tumor microenvironment. CELL DEATH & DISEASE, 10: 120. ISSN 2041-4889,
Full text not available from this repository. (Request a copy)Abstract
PD901, a MEK inhibitor, has been demonstrated of therapeutic efficacy against cholangiocarcinoma (CCA) harboring K-Ras oncogenic mutations. However, most CCA exhibit no K-Ras mutations. In the current study, we investigated the therapeutic potential of PD901, either alone or in combination with the pan-mTOR inhibitor MLN0128, for the treatment of K-Ras wild-type CCA in vitro using human CCA cell lines, and in vivo using AKT/YapS127A CCA mouse model. We discovered that in vitro, PD901 treatment strongly inhibited CCA cell proliferation, and combined PD901 and MLN0128 therapy further increased growth inhibition. In vivo, treatment of PD901 alone triggered tumor regression, which was not further increased when the two drugs were administered simultaneously. Mechanistically, PD901 efficiently hampered ERK activation in vitro and in vivo, leading to strong inhibition of CCA tumor cell cycle progression. Intriguingly, we discovered that PD901, but not MLN0128 treatment resulted in changes affecting the vasculature and cancer-associated fibroblasts in AKT/YapS127A mouse lesions. It led to the decreased hypoxia within tumor lesions, which may further enhance the anti-cell proliferation activities of PD901. Altogether, our study demonstrates that MEK inhibitors could be effective for the treatment of K-Ras wild-type CCA via inhibiting cell proliferation and modulating tumor microenvironment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | INTRAHEPATIC CHOLANGIOCARCINOMA; CLINICAL DEVELOPMENT; HYPOXIA; ACTIVATION; EXPRESSION; THERAPY; GROWTH; MTOR; MLN0128; STROMA; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Apr 2020 04:58 |
| Last Modified: | 22 Apr 2020 04:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27551 |
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