fostamatinib and Lymphoma--B-Cell

Posttransplant lymphoproliferative disorder (PTLD)-associated Epstein-Barr virus (EBV)+ B cell lymphomas are serious complications of solid organ and bone marrow transplantation. The EBV protein LMP2a, a B cell receptor (BCR) mimic, provides survival signals to virally infected cells through Syk tyrosine kinase. Therefore, we explored whether Syk inhibition is a viable therapeutic strategy for EBV-associated PTLD. We have shown that R406, the active metabolite of the Syk inhibitor fostamatinib, induces apoptosis and cell cycle arrest while decreasing downstream phosphatidylinositol-3'-kinase (PI3K)/Akt signaling in EBV+ B cell lymphoma PTLD lines in vitro. However, Syk inhibition did not inhibit or delay the in vivo growth of solid tumors established from EBV-infected B cell lines. Instead, we observed tumor growth in adjacent inguinal lymph nodes exclusively in fostamatinib-treated animals. In contrast, direct inhibition of PI3K/Akt significantly reduced tumor burden in a xenogeneic mouse model of PTLD without evidence of tumor growth in adjacent inguinal lymph nodes. Taken together, our data indicate that Syk activates PI3K/Akt signaling which is required for survival of EBV+ B cell lymphomas. PI3K/Akt signaling may be a promising therapeutic target for PTLD, and other EBV-associated malignancies.

Topics: Aminopyridines; Animals; Apoptosis; B-Lymphocytes; Cell Cycle; Cell Line, Tumor; Enzyme Activation; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Intracellular Signaling Peptides and Proteins; Lymph Nodes; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Mice; Mice, Inbred NOD; Mice, SCID; Morpholines; Oxazines; Phosphatidylinositol 3-Kinases; Postoperative Complications; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Signal Transduction; Syk Kinase; Transplantation, Heterologous