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Myeloma

The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells

Leukemia volume 25, pages 1891–1899 (2011)Cite this article

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Abstract

Janus kinases (JAKs) are involved in various signalling pathways exploited by malignant cells. In multiple myeloma (MM), the interleukin-6/JAK/signal transducers and activators of transcription (IL-6/JAK/STAT) pathway has been the focus of research for a number of years and IL-6 has an established role in MM drug resistance. JAKs therefore make a rational drug target for anti-MM therapy. CYT387 is a novel, orally bioavailable JAK1/2 inhibitor, which has recently been described. This preclinical evaluation of CYT387 for treatment of MM demonstrated that CYT387 was able to prevent IL-6-induced phosphorylation of STAT3 and greatly decrease IL-6- and insulin-like growth factor-1-induced phosphorylation of AKT and extracellular signal-regulated kinase in human myeloma cell lines (HMCL). CYT387 inhibited MM proliferation in a time- and dose-dependent manner in 6/8 HMCL, and this was not abrogated by the addition of exogenous IL-6 (3/3 HMCL). Cell cycling was inhibited with a G2/M accumulation of cells, and apoptosis was induced by CYT387 in all HMCL tested (3/3). CYT387 synergised in killing HMCL when used in combination with the conventional anti-MM therapies melphalan and bortezomib. Importantly, apoptosis was also induced in primary patient MM cells (n=6) with CYT387 as a single agent, and again synergy was seen when combined with conventional therapies.

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Acknowledgements

CYT387 was kindly provided by YM BioSciences, Australia. This study was supported by part funding from the Multiple Myeloma Research Foundation.

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Authors and Affiliations

  1. Myeloma Research Group, Malignant Haematology and Stem Cell Transplantation, Alfred Hospital, Melbourne, Victoria, Australia

    K A Monaghan, T Khong & A Spencer

  2. Department of Clinical Haematology, Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia

    K A Monaghan, T Khong & A Spencer

  3. YM BioSciences Australia, Melbourne, Victoria, Australia

    C J Burns

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  1. K A Monaghan
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Correspondence to A Spencer.

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Competing interests

Katherine A Monaghan, Tiffany Khong and Andrew Spencer declare no potential conflict of interest. Christopher J Burns is an employee of YM BioSciences, and holds equity in the company.

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Supplementary Information accompanies the paper on the Leukemia website

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Monaghan, K., Khong, T., Burns, C. et al. The novel JAK inhibitor CYT387 suppresses multiple signalling pathways, prevents proliferation and induces apoptosis in phenotypically diverse myeloma cells. Leukemia 25, 1891–1899 (2011). https://doi.org/10.1038/leu.2011.175

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