Abstract Non-Hodgkin lymphoma (NHL) is one of the most common cancers worldwide, representing 90% of malignant lymphomas. NHL is a diverse group of malignancies, and a subset of these lymphomas are caused by infection with the human gammaherpesvirus, Epstein-Barr virus (EBV). Many EBV-positive lymphomas are highly aggressive and rapidly develop resistance to treatment, leading to poor patient outcomes. Here, we identify the cellular kinase, NEK2, as a therapeutic target for EBV-positive NHL. We demonstrate NEK2 protein expression is increased in primary lymphocytes following EBV infection, NEK2 expression is significantly upregulated in EBV-positive NHL, and that NEK2 is necessary for the growth and survival of EBV-positive NHL. Inhibition of NEK2 resulted in lymphoma-specific cell death characterized by reactive oxygen species accumulation and gasdermin D cleavage. Additionally, protein levels of the major EBV oncoprotein, LMP1, were decreased following NEK2 inhibition. Furthermore, we demonstrate that MRP1 is the major drug resistance transporter protein in EBV-positive NHL. NEK2 inhibition reduced the expression and activity of cellular drug resistance transporter proteins including MRP1, leading to increased lymphoma cell chemosensitivity. Finally, using a humanized mouse model of EBV-driven lymphomagenesis, we demonstrate that NEK2 inhibition significantly decreased tumor burden and tumor incidence while prolonging survival in vivo. Taken together, our data suggest NEK2 inhibition as a promising treatment strategy for EBV-positive NHL. Citation Format: Maria C. White, Philip T. Lange, Blossom A. Damania, . NEK2 drives pathogenesis, drug resistance, and LMP1 expression in EBV-positive non-Hodgkin lymphoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7160.
White et al. (Fri,) studied this question.