WSU-FSCCL

PAK4-NAMPT Is Essential for Lymphoma Cell Survival

Non-Hodgkin's lymphomas (NHL) are diverse, with aggressive subtypes like DLBCL and MCL, and indolent ones like FL. All NHL subtypes can metastasize if untreated. Khan et al. investigated the potential of a dual inhibitor, KPT-9274, targeting PAK4 and NAMPT, to induce energy depletion, inhibit cell proliferation, and trigger apoptosis in various NHL subtypes.

IHC on tissue microarrays showed higher PAK4 expression in NHL primary tumors vs. normal lymph nodes (Fig. 1A). PAK4 staining correlated with the proliferation index (Ki67) in high-grade lymphomas but was lower in low-grade NHLs. Exposure of lymphoma cells to low nanomolar concentrations of the dual PAK4-NAMPT inhibitor KPT-9274 (Fig. 1B) inhibited cell proliferation (Fig. 1C), with EC₅₀ values of 95.17 nM in WSU-DLCL2 and 13.9 nM in WSU-FSCCL cells. To assess the effect on normal cells, PBMCs from a healthy, non-smoking donor were treated with KPT-9274 (0-750 nM) for 72 h. KPT-9274 did not significantly reduce cell viability even at 750 nM, with an EC₅₀ of 1836 nM for PBMCs, much higher than for WSU-DLCL2 and WSU-FSCCL cells. KPT-9274 activity is not restricted to lymphoma models; they have shown cancer cell selectivity with high micromolar EC₅₀s in normal peripheral lymphocytes and normal human pancreatic ductal epithelial cells (>500 nM). qRT-PCR results showed that KPT-9274 treatment reduced PAK4 and NAMPT expression in WSU-DLCL2 and WSU-FSCCL cells (Fig. 1D). These findings support their hypothesis that PAK4-NAMPT is critical for lymphoma cell survival and that targeting these proteins could be an effective strategy against these challenging diseases.