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Myeloma

The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival

Abstract

IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138+ cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.

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Acknowledgements

This work was supported by a grant from the National Institute of Health (R01 CA-055652) and AstraZeneca to RJ, WM Keck Foundation and Tim Nesvig Lymphoma Fellowships to AS, Ministry of Education, Youth and Sports of the Czech Republic (MSM0021622430) and Grant Agency of the Czech Republic (301/09/0587) to PK. We thank Drs Dennis Huszar and Michael Zinda from AstraZeneca R&D, Boston for providing AZD1480 and valuable suggestions, members of our laboratories for stimulating discussion and the Analytical Cytometry Core at City of Hope.

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Correspondence to A Scuto.

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This work was partially supported by AstraZeneca product of which, AZD1480, was studied in this work.

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Scuto, A., Krejci, P., Popplewell, L. et al. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. Leukemia 25, 538–550 (2011). https://doi.org/10.1038/leu.2010.289

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