EBV-Associated T and Natural Killer Cell Lymphoma Cells : mTOR Inhibitors

mTOR Inhibitors Induce Cell Cycle Arrest and Inhibit Tumor Growth in Epstein-Barr Virus-Associated T and Natural Killer Cell Lymphoma Cells
Purpose: Epstein-Barr virus (EBV) infects B cells, as well as T cells and NK cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells the mammalian/mechanistic target of rapamycin (mTOR) performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBV-associated T and NK cell lymphomas. Experimental Design: We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T and NK cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3 and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analog, CCI-779) against these cell lines in culture and in a murine xenograft model which was established by subcutaneous injection of SNK6 cells into NOG mice. Results: All EBV-positive and -negative T and NK cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors induced G1 cell-cycle arrest and inhibited cell proliferation in T and NK cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and-negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood. Conclusion: These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T and NK cell lymphoma.