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The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma

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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.

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Acknowledgements

This work was supported by a MMRF senior research grant award (to K.P); a grant to the Fritz Thyssen foundation (to M.S.R.); National Institutes of Health grants RO CA 50947, PO-1 CA 78378, and P50 CA 100707; and the American Cancer Society Clinical Research Professor Award (to K.C.A.). This work was also supported by the medical faculty of science of the University of Heidelberg, Germany.

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Authors and Affiliations

  1. Max-Eder-Group ‘Experimental Therapies for Hematologic Malignancies’, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany

    Iris Breitkreutz, Vianihuini Figueroa-Vazquez & Marc S. Raab

  2. LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA

    Iris Breitkreutz, Klaus Podar, Kenneth C. Anderson & Marc S. Raab

  3. Department of Medicine V, Heidelberg University Hospital, INF 410, 69120, Heidelberg, Germany

    Iris Breitkreutz & Marc S. Raab

  4. Department of Internal Medicine, University Hospital Krems, Karl Landsteiner University of Health Sciences, 3500, Krems, Austria

    Klaus Podar

  5. Bayer HealthCare Pharmaceuticals, Montville, 07045, NJ, USA

    Scott Wilhelm

  6. Department of Academic Haematology, St. James’s Hospital, Trinity College, St. James’s Hospital, Dublin 8, Ireland

    Patrick J. Hayden

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  1. Iris Breitkreutz
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  2. Klaus Podar
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  3. Vianihuini Figueroa-Vazquez
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  7. Marc S. Raab
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Correspondence to Marc S. Raab.

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Written informed consent of MM patients was obtained with approval of the institutional ethics committee according to the Declaration of Helsinki.

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Electronic supplementary material

Supplemental Figure 1

Regorafenib induces apoptosis in MM cells. MM cells were exposed to increasing concentrations of regorafenib for 4 h or 20 h, followed by immunoblot analysis of whole cell lysates with indicated antibodies. (PPTX 111 kb)

Supplemental Figure 2

Regorafenib in combination with CAL-101 synergistically inhibit signaling pathways. MM cells were exposed to increasing concentrations of regorafenib for 4 h or 20 h, followed by immunoblot analysis of whole cell lysates with indicated antibodies. (PPTX 87 kb)

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Breitkreutz, I., Podar, K., Figueroa-Vazquez, V. et al. The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma. Ann Hematol 97, 839–849 (2018). https://doi.org/10.1007/s00277-018-3237-5

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