Waldenström’s macroglobulinemia (WM), a rare subtype of non-Hodgkin lymphoma, is characterized by overproduction of immunoglobulin M (IgM) antibody by malignant B-cells.
B-cell antigen receptor (BCR) signaling plays a pivotal role in WM disease pathogenesis. Signaling through the BCR leads to activation of spleen tyrosine kinase (SYK) and downstream kinases that play a role in lymphoma pathobiology. The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib targets BCR-controlled signaling and integrin-mediated adhesion in WM cells, but some patients with WM become refractory to ibrutinib treatment. Because SYK signaling is upstream of BTK, it represents a plausible target for researchers to explore the effect of the SYK inhibitor R406, the active metabolite of fostamatinib, on BCR-mediated signaling and cell adhesion in WM.
In these preclinical studies, MWCL-1 cells were treated with R406, the selective p110δ inhibitor idelalisib, or with ibrutinib, at concentrations up to 10 µM and stimulated with anti-IgM antibodies or phorbol myristate acetate (PMA). The cells were transferred to plates coated with fibronectin to assess cell adhesion. For the proliferation assays, MWCL-1 cells or primary B-cells were pretreated with kinase inhibitors followed by stimulation of primary B-cells with anti-IgM.
Researchers found that anti-IgM or PMA alone stimulated the adhesion of MWCL-1 on fibronectin. The addition of R406 inhibited IgM-mediated cell adhesion to a degree comparable with ibrutinib. However, neither compound affected PMA-induced cell adhesion, indicating that the effect on IgM-mediated cell adhesion was not due to toxicity. Lack of off-target toxicity was further confirmed in the MWCL-1 proliferation assays where the compounds showed less potency than in BCR-mediated assays. Similar inhibition of adhesion and proliferation was seen with idelalisib.
These preclinical studies confirm that SYK is involved in BCR-mediated signaling and cell adhesion in WM. R406 was as effective as ibrutinib in blocking WM cell adhesion. As SYK inhibition takes place upstream of PI3K, idelalisib-mediated inhibition of adhesion further confirmed the role of SYK. These studies provide a rationale for investigating fostamatinib as a potential treatment option in WM.
Abstract e19047; Markovtsov V, et al.