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

A. Scuto, P. Krejci, L. Popplewell, J. Wu, Y. Wang, M. Kujawski, C. Kowolik, H. Xin, L. Chen, Y. Wang, L. Kretzner, H. Yu, W. R. Wilcox, Y. Yen, S. Forman, R. Jove

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)538-550
Number of pages13
JournalLeukemia
Volume25
Issue number3
DOIs
Publication statusPublished - Jan 1 2011
Externally publishedYes

Fingerprint

Cell Survival
Growth
Cyclin D2
Multiple Myeloma
Mesenchymal Stromal Cells
Interleukin-6
Cell Line
Critical Pathways
Proxy
AZD 1480
Heterografts
Cultured Cells
Signal Transduction
Blood Cells
Cell Death
Phosphorylation
Cell Proliferation
Apoptosis
Survival
Genes

Keywords

  • FGFR3
  • JAK2
  • myeloma
  • STAT3

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. / Scuto, A.; Krejci, P.; Popplewell, L.; Wu, J.; Wang, Y.; Kujawski, M.; Kowolik, C.; Xin, H.; Chen, L.; Wang, Y.; Kretzner, L.; Yu, H.; Wilcox, W. R.; Yen, Y.; Forman, S.; Jove, R.

In: Leukemia, Vol. 25, No. 3, 01.01.2011, p. 538-550.

Research output: Contribution to journalArticle

Scuto, A, Krejci, P, Popplewell, L, Wu, J, Wang, Y, Kujawski, M, Kowolik, C, Xin, H, Chen, L, Wang, Y, Kretzner, L, Yu, H, Wilcox, WR, Yen, Y, Forman, S & Jove, R 2011, 'The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival', Leukemia, vol. 25, no. 3, pp. 538-550. https://doi.org/10.1038/leu.2010.289
Scuto, A. ; Krejci, P. ; Popplewell, L. ; Wu, J. ; Wang, Y. ; Kujawski, M. ; Kowolik, C. ; Xin, H. ; Chen, L. ; Wang, Y. ; Kretzner, L. ; Yu, H. ; Wilcox, W. R. ; Yen, Y. ; Forman, S. ; Jove, R. / The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival. In: Leukemia. 2011 ; Vol. 25, No. 3. pp. 538-550.
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AU - Kretzner, L.

AU - Yu, H.

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