figure
posted on 2024-04-09, 15:20 authored by Maria C. White, Jason P. Wong, Blossom Damania JH295 treatment sensitizes viral and non-viral lymphomas to chemotherapy and has a synergistic effect on lymphoma cell death. A–C, Viability of PEL cells over time treated with vehicle control (DMSO, black bars), 2.2 µmol/L vinblastine (red bars), or ≤ 1.0 µmol/L JH295 (navy bars). Data are plotted as individual values of three independent biological replicates performed in triplicate and normalized to the 0-hour luminescence values for each treatment group. Data represent mean ± SEM and were analyzed using two-way ANOVA with Tukey multiple comparisons. ns, not significant; ****, P < 0.0001; ***, P < 0.0006; **, P = 0.0092; *, P < 0.04. D–I, Viability of lymphoma cells following 72 hours of treatment with DMSO (black boxes), rapamycin (salmon boxes), JH295 (aquamarine boxes), or rapamycin + JH295 (gray boxes). Data are plotted as individual values of three independent biological replicates performed in triplicate and normalized to the corresponding 0-hour luminescence values. Data were analyzed using one-way ANOVA with Sidak multiple comparisons. ****, P < 0.0001; ***, P = 0.0002; **, P < 0.007. D–F, virus-associated PEL cell lines. G, Nonviral DLBCL cell line. H–I, Nonviral mantle cell lymphoma cell lines.
Funding
HHS | National Institutes of Health (NIH)
American Cancer Society (ACS)
History
ARTICLE ABSTRACT
Non–Hodgkin lymphoma (NHL) is a common cancer in both men and women and represents a significant cancer burden worldwide. Primary effusion lymphoma (PEL) is a subtype of NHL infected with Kaposi sarcoma–associated herpesvirus (KSHV). PEL is an aggressive and lethal cancer with no current standard of care, owing largely to its propensity to develop resistance to current chemotherapeutic regimens. Here, we report a reliance of KSHV-positive PEL on the mitotic kinase, NEK2, for survival. Inhibition of NEK2 with the inhibitor, JH295, resulted in caspase 3–mediated apoptotic cell death of PEL. Furthermore, NEK2 inhibition significantly prolonged survival and reduced tumor burden in a PEL mouse model. We also demonstrate that the ABC transporter proteins, MDR1 and MRP, are most active in PEL and that inhibition of NEK2 in PEL reduced the expression and activity of these ABC transporter proteins, which are known to mediate drug resistance in cancer. Finally, we report that JH295 treatment sensitized lymphomas to other chemotherapeutic agents such as rapamycin, resulting in enhanced cancer cell death. Overall, these data offer important insight into the mechanisms underlying PEL survival and drug resistance, and suggest that NEK2 is a viable therapeutic target for PEL.
The mitotic kinase, NEK2, is important for the survival of KSHV-positive PEL. NEK2 inhibition resulted in PEL apoptosis and reduced tumor burden in a mouse model. NEK2 inhibition also reduced drug resistance.
