Song, Xinhua and Liu, Xianqiong and Wang, Haichuan and Wang, Jingxiao and Qiao, Yu and Cigliano, Antonio and Utpatel, Kirsten and Ribback, Silvia and Pilo, Maria G. and Serra, Marina and Gordan, John D. and Che, Li and Zhang, Shanshan and Cossu, Antonio and Porcu, Alberto and Pascale, Rosa M. and Dombrowski, Frank and Hu, Hongbo and Calvisi, Diego F. and Evert, Matthias and Chen, Xin (2019) Combined CDK4/6 and Pan-mTOR Inhibition Is Synergistic Against Intrahepatic Cholangiocarcinoma. CLINICAL CANCER RESEARCH, 25 (1). pp. 403-413. ISSN 1078-0432, 1557-3265
Full text not available from this repository. (Request a copy)Abstract
Purpose: Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer type, lacking effective therapies and associated with a dismal prognosis. Palbociclib is a selective CDK4/6 inhibitor, which has been shown to suppress cell proliferation in many experimental cancer models. Recently, we demonstrated that pan-mTOR inhibitors, such as MLN0128, effectively induce apoptosis, although have limited efficacy in restraining proliferation of ICC cells. Here, we tested the hypothesis that palbociclib, due to its antproliferative properties in many cancer types, might synergize with MLN0128 to impair ICC growth. Experimental Design: Human ICC cell lines and the AKT/YapS127A ICC mouse model were used to test the therapeutic efficacy of palbociclib and MLN0128, either alone or in combination. Results: Administration of palbociclib suppressed in vitro ICC cell growth by inhibiting cell-cycle progression. Concomitant administration of palbociclib and MLN0128 led to a pronounced, synergistic growth constraint of ICC cell lines. Furthermore, while treatment with palbociclib or MLN0128 alone resulted in tumor growth reduction in AKT/YapS127A mice, a remarkable tumor regression was achieved when the two drugs were administered simultaneously. Mechanistically, palbociclib was found to potentiate MLN0128 mTOR inhibition activity, whereas MLN0128 prevented the upregulation of cyclin D1 induced by palbociclib treatment. Conclusions: Our study indicates the synergistic activity of palbociclib and MLN0128 in inhibiting ICC cell proliferation. Thus, combination of CDK4/6 and mTOR inhibitors might represent a novel, promising, and effective therapeutic approach against human ICC.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CYCLIN-DEPENDENT KINASES; CELL-CYCLE; THERAPEUTIC TARGETS; CANCER; COMBINATION; GROWTH; TRANSCRIPTION; PALBOCICLIB; ACTIVATION; RESISTANCE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Apr 2020 06:02 |
| Last Modified: | 28 Apr 2020 06:02 |
| URI: | https://pred.uni-regensburg.de/id/eprint/27923 |
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