Targeting the Spleen Tyrosine Kinase with Fostamatinib as a Strategy against Waldenström Macroglobulinemia.
OBJECTIVE
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.


METHODS
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.
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Isere
I
Kuiatse
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Veerabhadran
V
Baladandayuthapani
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Heather Y
HY
Lin
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Sheeba K
SK
Thomas
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Chad C
CC
Bjorklund
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Donna M
DM
Weber
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Michael
M
Wang
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jatin J
JJ
Shah
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Xing-Ding
XD
Zhang
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Richard J
RJ
Jones
Division of Hematology, Mayo Clinic, Rochester, Minnesota.
Stephen M
SM
Ansell
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Guang
G
Yang
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Steven P
SP
Treon
Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. rorlowsk@mdanderson.org.
Robert Z
RZ
Orlowski
D000631:Aminopyridines; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D009025:Morpholines; D010078:Oxazines / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage*; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects; D000072377:Syk Kinase; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
D000631:Aminopyridines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C523665:fostamatinib