Journal Article

DKFZ-2018-00432

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma.

Breitkreutz, I. (First author)DKFZ* ; Podar, K.DKFZ* ; Figueroa-Vazquez, V. ; Wilhelm, S. ; Hayden, P. J. ; Anderson, K. C.DKFZ* ; Raab, M.-S. (Last author)DKFZ*

2018
Springer61936 Berlin

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Please use a persistent id in citations: doi:10.1007/s00277-018-3237-5

Abstract: A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations. Regorafenib overcomes the growth advantage conferred by a stroma cell MM and an endothelial cell MM, co-culture systems, and abrogates growth factor-stimulated MEK, ERK, and AKT phosphorylation at nanomolar to micromolar concentrations. Moreover, it inhibits endothelial cell growth and tubule formation, abrogates both VEGF secretion and VEGF-induced MM cell migration, inhibits osteoclastogenesis, and shows synergistic cytotoxicity with dexamethasone, the immunomodulatory drug pomalidomide, and the p110δ inhibitor idelalisib. Most importantly, regorafenib significantly delays tumor growth in a xenograft mouse model of human MM. These results provide the rationale for further clinical evaluation of regorafenib, alone and in combination, in the treatment of MM.

Keyword(s): Phenylurea Compounds ; Protein Kinase Inhibitors ; Pyridines ; regorafenib

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Contributing Institute(s):

1. Experimentelle Therapien hämatologischer Neoplasien (G170)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2018

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Database coverage:
; BIOSIS Previews ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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