Research Papers:

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

Maria Grazia Refolo, Rosalba D’Alessandro, Catia Lippolis, Nicola Carella, Aldo Cavallini, Caterina Messa and Brian Irving Carr _

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Oncotarget. 2017; 8:103465-103476. https://doi.org/10.18632/oncotarget.21403

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Maria Grazia Refolo1,*, Rosalba D’Alessandro1,*, Catia Lippolis1, Nicola Carella1, Aldo Cavallini1, Caterina Messa1 and Brian Irving Carr2

1Laboratory of Cellular and Molecular Biology, Department of Clinical Pathology, National Institute of Gastroenterology, “S. De Bellis” Research Hospital, Castellana Grotte, BA, Italy

2Visiting Professor, Program for Targeted Experimental Therapeutics, Izmir Biomedicine and Genome Center, Dokuz Eylul University, Izmir, Turkey

*These authors have contributed equally to this work

Correspondence to:

Brian Irving Carr, email: [email protected]

Caterina Messa, email: [email protected]

Keywords: combination therapy, synergism, regorafenib, vitamin K1, insulin-like growth factor receptor

Received: June 16, 2017    Accepted: September 13, 2017    Published: September 30, 2017


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.

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