Identification of RP‐54745, an IL‐1 Inhibitor Displaying Anticancer Activities for KSHV‐Related Primary Effusion Lymphoma

ABSTRACT Kaposi's sarcoma‐associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including primary effusion lymphoma (PEL), usually seen in immunocompromised patients while lack of effective therapeutic options. Interleukin‐1 (IL‐1) family is a major mediator for inflammatory responses and has functional role in both innate and adaptive immunity. We previously showed high activation of multiple IL‐1 signaling molecules during KSHV latent and lytic stages, as well as in clinical samples from patients with KSHV‐related malignancies. In the current study, we identified RP‐54745, a potential antirheumatic compound as IL‐1 inhibitor, effectively repressed KSHV + PEL cell growth through inducing tumor cell apoptosis. By using an established PEL xenograft model, we found that RP‐54745 treatment suppressed tumor expansion in mice. Also, RP‐54745 treatment significantly reduced hyperinflammation in tumor microenvironment including myeloid cells and neutrophils infiltration, as well as blocking IL‐1 signaling molecules expression in vivo. In addition, our transcriptome analysis revealed novel cellular genes and mechanisms for anticancer activities of RP‐54745. Taken together, our data indicate targeting IL‐1 production and signaling may represent promising therapeutic strategies against these virus‐associated diseases.