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

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

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1190-1202
Number of pages13
JournalOncogene
Volume29
Issue number8
DOIs
StatePublished - Feb 2010

Keywords

  • Angiogenesis
  • Apoptosis
  • Microenvironment
  • Myeloma
  • Proliferation
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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