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.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide [1, 2]
We investigated the effects of the benzyl styryl sulfone rigosertib (RGS, ON-01910) on viability of human hepatocellular carcinoma (HCC) cell lines (PLC, Hep3B) in vitro
Within the Asian population, high Harvey rat sarcoma virus oncogene (HRAS) expression significantly (p < 0.05) correlated with low patient overall survival (Figure 5B, right panel). Both polo-like kinase 1 (PLK1) and RAS are targets of the novel and effective small molecule inhibitor rigosertib (Figures 1–3), and we found that PLK1 and HRAS are commonly upregulated in HCC (Figure 4) and independently affect patient overall survival (Figure 5) with interesting differences among different ethnic background
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide [1, 2]. Sorafenib is the only successful first-line therapeutic option for patients with advanced disease [3,4,5]. The RAS-RAF-ERK-pathway serves as the major target of the effects mediated by the multi-kinase inhibitors sorafenib and regorafenib, underlining the importance of MAPK-signaling in HCC [3, 6, 7]. Disease progression after sorafenib treatment occurs in the majority of treated patients [5, 8, 9]. Regorafenib is the only approved systemic second-line treatment shown to provide a modest survival benefit (2.8 months) in www.impactjournals.com/oncotarget. HCC patients progressing on sorafenib treatment [10]. Novel and more successful therapeutic approaches are urgently needed [2, 3]
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