Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs.
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.
Ramakrishnan
V
V
Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA.
Timm
M
M
Haug
J L
JL
Kimlinger
T K
TK
Wellik
L E
LE
Witzig
T E
TE
Rajkumar
S V
SV
Adjei
A A
AA
Kumar
S
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D009101:Multiple Myeloma / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048490:raf Kinases / Q000037:antagonists & inhibitors*
D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D050796:STAT3 Transcription Factor; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000077157:Sorafenib; D040262:Receptors, Vascular Endothelial Growth Factor; D048490:raf Kinases