Targeting the spleen tyrosine kinase with fostamatinib as a strategy against Waldenström Macroglobulinemia

Isere Kuiatse, Veerabhadran Baladandayuthapani, Heather Y. Lin, Sheeba K. Thomas, Chad C. Bjorklund, Donna M. Weber, Michael Wang, Jatin J. Shah, Xing Ding Zhang, Richard J. Jones, Stephen Maxted Ansell, Guang Yang, Steven P. Treon, Robert Z. Orlowski

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Purpose: Waldenström macroglobulinemia (WMG) is a lymphoproliferative disorder characterized by good initial responses to standard therapeutics, but only a minority of patients achieve complete remissions, and most inevitably relapse, indicating a need for novel agents. B-cell receptor signaling has been linked to clonal evolution in WMG, and Spleen tyrosine kinase (Syk) is overexpressed in primary cells, suggesting that it could be a novel and rational target. Experimental Design: We studied the impact of the Syk inhibitor fostamatinib on BCWM.1 and MWCL-1 WMG-derived cell lines both in vitro and in vivo, as well as on primary patient cells. Results: In WMG-derived cell lines, fostamatinib induced a time-and dose-dependent reduction in viability, associated with activation of apoptosis. At the molecular level, fostamatinib reduced activation of Syk and Bruton's tyrosine kinase, and also downstream signaling through MAPK kinase (MEK), p44/42 MAPK, and protein kinase B/Akt. As a single agent, fostamatinib induced tumor growth delay in an in vivo model of WMG, and reduced viability of primary WMG cells, along with inhibition of p44/42 MAPK signaling. Finally, fostamatinib in combination with other agents, including dexamethasone, bortezomib, and rituximab, showed enhanced activity. Conclusions: Taken together, these data support the translation of approaches targeting Syk with fostamatinib to the clinic for patients with relapsed and possibly even newly diagnosed WMG.

Original languageEnglish (US)
Pages (from-to)2538-2545
Number of pages8
JournalClinical Cancer Research
Volume21
Issue number11
DOIs
StatePublished - Jun 1 2015

    Fingerprint

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kuiatse, I., Baladandayuthapani, V., Lin, H. Y., Thomas, S. K., Bjorklund, C. C., Weber, D. M., Wang, M., Shah, J. J., Zhang, X. D., Jones, R. J., Ansell, S. M., Yang, G., Treon, S. P., & Orlowski, R. Z. (2015). Targeting the spleen tyrosine kinase with fostamatinib as a strategy against Waldenström Macroglobulinemia. Clinical Cancer Research, 21(11), 2538-2545. https://doi.org/10.1158/1078-0432.CCR-14-1462