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

J Med Virol. 2025 Feb;97(2):e70200. doi: 10.1002/jmv.70200.

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.

Keywords: IL‐1; KSHV; PEL; lymphoma.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Herpesvirus 8, Human* / drug effects
  • Herpesvirus 8, Human* / genetics
  • Humans
  • Interleukin-1* / antagonists & inhibitors
  • Interleukin-1* / genetics
  • Interleukin-1* / metabolism
  • Lymphoma, Primary Effusion* / drug therapy
  • Lymphoma, Primary Effusion* / virology
  • Mice
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Interleukin-1
  • Antineoplastic Agents