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  • Original Article
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Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs

Oncogene volume 29, pages 1190–1202 (2010)Cite this article

Abstract

Multiple myeloma is characterized by increased bone marrow neovascularization driven in part by vascular endothelial growth factor (VEGF). In addition, the Ras/Raf/MEK/ERK pathway is critical for the proliferation of myeloma cells and is often upregulated. Sorafenib (Nexavar) is a novel multi-kinase inhibitor that acts predominantly through inhibition of Raf-kinase and VEGF receptor 2, offering the potential for targeting two important aspects of disease biology. In in vitro studies, sorafenib-induced cytotoxicity in MM cell lines as well as freshly isolated patient myeloma cells. It retained its activity against MM cells in co-culture with stromal cells or with interleukin-6, VEGF or IGF; conditions mimicking tumor microenvironment. Examination of cellular signaling pathways showed downregulation of Mcl1 as well as decreased phosphorylation of the STAT3 and MEK/ERK, as potential mechanisms of its anti-tumor effect. Sorafenib induces reciprocal upregulation of Akt phosphorylation; and simultaneous inhibition of downstream mTOR with rapamycin leads to synergistic effects. Sorafenib also synergizes with drugs such as proteasome inhibitors and steroids. In a human in vitro angiogenesis assay, sorafenib showed potent anti-angiogenic activity. Sorafenib, through multiple mechanisms exerts potent anti-myeloma activity and these results favor further clinical evaluation and development of novel sorafenib combinations.

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Acknowledgements

We acknowledge Roberta DeGoey and Christy Finke for their assistance with processing of tumor cells and all of the patients who provided us with the tumor samples. This work was supported by Mayo Clinic Hematologic Malignancies Program, CR20 Award from Mayo Foundation and Career Development Award from Lymphoma SPORE. Sorafenib was provided through CTEP drug evaluation program by Bayer Pharmaceuticals.

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  1. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    V Ramakrishnan, M Timm, J L Haug, T K Kimlinger, L E Wellik, T E Witzig, S V Rajkumar & S Kumar

  2. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    A A Adjei

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  1. V Ramakrishnan
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Correspondence to S Kumar.

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Ramakrishnan, V., Timm, M., Haug, J. et al. Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs. Oncogene 29, 1190–1202 (2010). https://doi.org/10.1038/onc.2009.403

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