INTERLEUKIN-12 Enhances the antitumor effect of the tyrosine kinase inhibitor AG-490 in a murine myeloma model

Abstract

Constitutive activation of Jak kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3) has been found in various hematopoietic malignancies and solid tumors. In this study, we investigated the effect of blocking JAK/STAT signaling with AG-490 on the survival of murine myeloma cells and on interleukin-12 (IL-12)-mediated immune response in a syngenic murine model. We found that in vivo treatment with AG-490 selectively induced apoptosis of the murine myeloma cell lines that harbored constitutively activated STAT3. Because the murine myeloma tumors are fast growing and poorly immunogenic, AG-490-induced tumor regression was only transient. In contrast to AG-490, cytokine-based immunotherapy usually generates long-term antitumor immunity but fails to induce regression of established tumors. However, many cytokines, including IL-12, are known to signal through JAK/STAT pathways. Our results demonstrate that in vivo administration of AG-490 does not reduce IL-12-mediated macrophage and splenocyte activation. Furthermore, combinational therapy with AG-490 and IL-12 resulted in prolonged tumor regression. These results suggest that combining AG-490 and IL-12 may posses clinical potential as an effective approach for treatment of human cancers harboring constitutively activated JAK/STAT signaling.