Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option

Journal article


Publication Details

Author(s): Dietrich P, Freese K, Mahli A, Thasler WE, Hellerbrand C, Boßerhoff AK
Journal: Oncotarget
Publication year: 2018
Volume: 9
Journal issue: 3
Pages range: 3605-3618
ISSN: 1949-2553


Abstract

Inhibition of RAS-RAF-ERK-signaling is a major mechanism mediated by the multi-kinase inhibitors sorafenib and regorafenib, the only effective therapeutic approaches for advanced hepatocellular carcinoma (HCC). This underlines the importance of RAS-RAF-ERK-signaling in HCC. Most RAS isoforms were not yet described to play crucial roles in HCC. However, several studies indicate that the HRAS isoform can function as potent oncogene in HCC, but pharmacologic RAS inhibition has not yet been investigated. Moreover, the cell cycle promoting polo-like kinase 1 (PLK1) is an increasingly recognized therapeutic target in HCC that can be activated by RAS-RAF-signaling. A recently developed small molecule inhibitor, ON-01910 ("rigosertib", RGS), was shown to interfere with both RAS- and PLK1-signaling. The aim of this study was to analyze the effects of RGS in HCC and to assess PLK1 and HRAS expression in HCC. RGS treatment reduced cell proliferation and induced cell cycle arrest in human HCC cell lines in vitro. Moreover, RGS strongly inhibited both ERK- and AKT-activation in HCC cells, indicating disruption of RAS-signaling. Analysis of HCC patient data showed that PLK1 and HRAS expression levels are upregulated during HCC development and in advanced HCC, respectively. High expression levels of PLK1 significantly correlated with poor patient survival. Moreover, high expression of both PLK1 and HRAS revealed combined effects on patient outcome. This underscores the importance of these genes and associated pathways in HCC. We newly demonstrate the therapeutic potential of RGS in HCC by inhibition of both PLK1 activation and major RAS-pathways, revealing a novel therapeutic "dual-hit" approach for HCC.


FAU Authors / FAU Editors

Boßerhoff, Anja Katrin Prof. Dr.
Lehrstuhl für Biochemie und Molekulare Medizin
Dietrich, Peter Dr.
Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
Freese, Kim
Lehrstuhl für Biochemie und Molekulare Medizin
Hellerbrand, Claus Prof. Dr.
Professur für Biochemie und Molekulare Pathobiologie
Mahli, Abdo Dr.
Lehrstuhl für Biochemie und Molekulare Medizin


External institutions with authors

Ludwig-Maximilians-Universität (LMU)


How to cite

APA:
Dietrich, P., Freese, K., Mahli, A., Thasler, W.E., Hellerbrand, C., & Boßerhoff, A.K. (2018). Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option. Oncotarget, 9(3), 3605-3618. https://dx.doi.org/10.18632/oncotarget.23188

MLA:
Dietrich, Peter, et al. "Combined effects of PLK1 and RAS in hepatocellular carcinoma reveal rigosertib as promising novel therapeutic "dual-hit" option." Oncotarget 9.3 (2018): 3605-3618.

BibTeX: 

Last updated on 2019-25-04 at 14:57