TY - JOUR
T1 - Targeting the spleen tyrosine kinase with fostamatinib as a strategy against Waldenström Macroglobulinemia
AU - Kuiatse, Isere
AU - Baladandayuthapani, Veerabhadran
AU - Lin, Heather Y.
AU - Thomas, Sheeba K.
AU - Bjorklund, Chad C.
AU - Weber, Donna M.
AU - Wang, Michael
AU - Shah, Jatin J.
AU - Zhang, Xing Ding
AU - Jones, Richard J.
AU - Ansell, Stephen M.
AU - Yang, Guang
AU - Treon, Steven P.
AU - Orlowski, Robert Z.
N1 - Publisher Copyright:
© 2015 AACR.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-14-1462
DO - 10.1158/1078-0432.CCR-14-1462
M3 - Article
C2 - 25748087
AN - SCOPUS:84941985199
SN - 1078-0432
VL - 21
SP - 2538
EP - 2545
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -