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Multiple Myeloma, Gammopathies

Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma

Leukemia volume 31, pages 1715–1726 (2017)Cite this article

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Abstract

The PIM kinase family (PIM1, 2 and 3) have a central role in integrating growth and survival signals, and are expressed in a wide range of solid and hematological malignancies. We now confirm that PIM2 is overexpressed in multiple myeloma (MM) patients, and within MM group it is overexpressed in the high-risk MF subset (activation of proto-oncogenes MAF/MAFB). This is consistent with our finding of PIM2’s role in key signaling pathways (IL-6, CD28 activation) that confer chemotherapy resistance in MM cells. These studies have identified a novel PIM2-selective non-ATP competitive inhibitor (JP11646) that has a 4 to 760-fold greater suppression of MM proliferation and viability than ATP-competitive PIM inhibitors. This increased efficacy is due not only to the inhibition of PIM2 kinase activity, but also to a novel mechanism involving specific downregulation of PIM2 mRNA and protein expression not seen with the ATP competitive inhibitors. Treatment with JP11646 in xenogeneic myeloma murine models demonstrated significant reduction in tumor burden and increased median survival. Altogether our findings suggest the existence of previously unrecognized feedback loop(s) where PIM2 kinase activity regulates PIM2 gene expression in malignant cells, and that JP11646 represents a novel class of PIM2 inhibitors that interdicts this feedback.

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Acknowledgements

JRN, KB, JC, TH and CB performed the experiments and derived the data shown. JRN wrote the paper. JC, CB, GF and KPL supervised the work performed, and reviewed and edited the manuscript.

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Author notes

  1. G Fetterly

    Present address: 6Current address: Kinex Pharmaceuticals, Buffalo, NY 14203, USA.,

Authors and Affiliations

  1. Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, USA

    J R Nair, T Howell & K P Lee

  2. Jasco Pharmaceuticals, Woburn, MA, USA

    J Caserta & C Baldino

  3. Boston Biomedical, Inc., Cambridge, MA, USA

    J Caserta

  4. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA

    K Belko

  5. Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA

    G Fetterly & K P Lee

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  1. J R Nair
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Correspondence to K P Lee.

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CB and JC are scientific co-founders and the president and vice president respectively of Jasco Pharmaceuticals. The other authors declare no conflicts of interest. This work was funded by Jasco Pharmaceuticals, R01 CA121044 and R01 AI100157.

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Nair, J., Caserta, J., Belko, K. et al. Novel inhibition of PIM2 kinase has significant anti-tumor efficacy in multiple myeloma. Leukemia 31, 1715–1726 (2017). https://doi.org/10.1038/leu.2016.379

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