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Oncotarget. 2017 Sep 30;8(61):103465-103476. doi: 10.18632/oncotarget.21403. eCollection 2017 Nov 28.

IGF-1R tyrosine kinase inhibitors and Vitamin K1 enhance the antitumor effects of Regorafenib in HCC cell lines.

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Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, "S. De Bellis" Research Hospital, Castellana Grotte, BA, Italy.
Visiting Professor, Program for Targeted Experimental Therapeutics, Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey.


The recent RESORCE trial showed that treatment with Regorafenib after Sorafenib failure provided a significant improvement in overall survival in HCC patients. Preclinical and clinical trial data showed that Regorafenib is a more potent drug than Sorafenib. In this study we aimed at improving Regorafenib actions and at reducing its toxicity, by targeting parallel pathways or by combination with Vitamins K (VKs). We investigated the effects of Regorafenib administrated at low concentrations and in combination with either VK1 and/or with GSK1838705A or OSI-906, two IGF1-R inhibitors, on HCC cell growth and motility. Our results showed that both IGF1-R inhibitors potentiated the antiproliferative and pro-apoptotic effects of Regorafenib and/or VK1 in HCC cell lines. Moreover we provide evidence that the combined treatment with IG1-R antagonists and Regorafenib (and/or VK1) also caused a significant reduction and depolymerization of actin resulting in synergistic inhibition exerted on cell migration. Thus, simultaneous blocking of MAPK and PI3K/Akt cascades with IGF1-R inhibitors plus Regorafenib could represent a more potent approach for HCC treatment.


combination therapy; insulin-like growth factor receptor; regorafenib; synergism; vitamin K1

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