The Syk Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of EBV-Associated Lymphoma

Epstein-Barr virus (EBV) is associated with the development of several cancers including Burkitt's Lymphoma, Hodgkin Lymphoma, Nasopharyngeal and Gastric Carcinomas. EBV-encoded Latent Membrane Protein 2A (LMP2A), a BCR mimic, is expressed in cancer cells and is essential for transformation, migration and inhibition of differentiation. LMP2A/λ-MYC double transgenic mice develop splenomegaly and lymphoma much faster than mice that express Myc only. LMP2A induces cancer phenotype by recruiting and activating BCR signaling components such as Lyn and Syk kinases to the SH2 motifs found on its N terminal cytoplasmic domain. In this study, we explored inhibition of Syk kinase activity with a novel Syk/FLT-3 inhibitor TAK-659, in lymphomas from these transgenic mice to assess SYK inhibition as a potential therapeutic strategy for EBV-associated malignancies.

The cell lines developed from LMP2A/Myc transgenic mice derived lymphomas showed higher basal pSYK levels than Myc lymphoma cell lines. TAK-659 treatment resulted in early apoptosis within 8hrs in LMP2A/Myc lymphoma cells in comparison to 24 hrs in Myc lymphoma cells. In both pre-tumor and tumor transfer models in vivo, compared with placebo and Myc tumors, LMP2A/MYC mice treated with TAK-659 did not develop splenomegaly and tumor development was totally inhibited in these mice indicating SYK signaling is essential for tumor development in LMP2A/Myc mice. In addition, metastasis of tumor cells into BM was abrogated. TAK-659 killed tumor cells but not host cells in spleen and tumors.

Taken together our data show that TAK-659, even in low nanomolar concentrations, inhibits pSYK and induces apoptosis in LMP2A/Myc tumor cells. It also inhibits splenomegaly and tumor development in our autochthonous and syngeneic tumor transfer models of EBV-associated lymphoma by targeting tumor cells while sparing non-tumor cells. Therefore, TAK-659 may provide an effective therapeutic option for the treatment of EBV-associated malignancies and should be explored further in clinical trials.