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Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade.

Publication ,  Journal Article
Zheng, J; Sha, Y; Roof, L; Foreman, O; Lazarchick, J; Venkta, JK; Kozlowski, C; Gasparetto, C; Chao, N; Ebens, A; Hu, J; Kang, Y
Published in: Cancer Lett
January 2019

Multiple myeloma remains an incurable disease, and continued efforts are required to develop novel agents and novel drug combinations with more effective anti-myeloma activity. Here, we show that the pan-PIM kinase inhibitors SGI1776 and CX6258 exhibit significant anti-myeloma activity and that combining a pan-PIM kinase inhibitor with the immunomodulatory agent lenalidomide in an in vivo myeloma xenograft mouse model resulted in synergistic myeloma cell killing without additional hematologic or hepatic toxicities. Further investigations indicated that treatment with a pan-PIM kinase inhibitor promoted increased ubiquitination and subsequent degradation of IKZF1 and IKZF3, two transcription factors crucial for survival of myeloma cells. Combining a pan-PIM kinase inhibitor with lenalidomide led to more effective degradation of IKZF1 and IKZF3 in multiple myeloma cell lines as well as xenografts of myeloma tumors. We also demonstrated that treatment with a pan-PIM kinase inhibitor resulted in increased expression of cereblon, and that knockdown of cereblon via a shRNA lentivirus abolished the effects of PIM kinase inhibition on the degradation of IKZF1 and IKZF3 and myeloma cell apoptosis, demonstrating a central role of cereblon in pan-PIM kinase inhibitor-mediated down-regulation of IKZF1 and IKZF3 and myeloma cell killing. These data elucidate the mechanism of pan-PIM kinase inhibitor mediated anti-myeloma effect and the rationale for the synergy observed with lenalidomide co-treatment, and provide justification for a clinical trial of the combination of pan-PIM kinase inhibitors and lenalidomide for the treatment of multiple myeloma.

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Published In

Cancer Lett

DOI

EISSN

1872-7980

Publication Date

January 2019

Volume

440-441

Start / End Page

1 / 10

Location

Ireland

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitin-Protein Ligases
  • Signal Transduction
  • Pyridazines
  • Proto-Oncogene Proteins c-pim-1
  • Protein Kinase Inhibitors
  • Proteasome Endopeptidase Complex
  • Peptide Hydrolases
  • Oncology & Carcinogenesis
  • Multiple Myeloma
 

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Zheng, J., Sha, Y., Roof, L., Foreman, O., Lazarchick, J., Venkta, J. K., … Kang, Y. (2019). Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. Cancer Lett, 440441, 1–10. https://doi.org/10.1016/j.canlet.2018.10.003
Zheng, Jing, Yonggang Sha, Logan Roof, Oded Foreman, John Lazarchick, Jagadish Kummetha Venkta, Cleopatra Kozlowski, et al. “Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade.Cancer Lett 440–441 (January 2019): 1–10. https://doi.org/10.1016/j.canlet.2018.10.003.
Zheng J, Sha Y, Roof L, Foreman O, Lazarchick J, Venkta JK, et al. Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. Cancer Lett. 2019 Jan;440–441:1–10.
Zheng, Jing, et al. “Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade.Cancer Lett, vol. 440–441, Jan. 2019, pp. 1–10. Pubmed, doi:10.1016/j.canlet.2018.10.003.
Zheng J, Sha Y, Roof L, Foreman O, Lazarchick J, Venkta JK, Kozlowski C, Gasparetto C, Chao N, Ebens A, Hu J, Kang Y. Pan-PIM kinase inhibitors enhance Lenalidomide's anti-myeloma activity via cereblon-IKZF1/3 cascade. Cancer Lett. 2019 Jan;440–441:1–10.
Journal cover image

Published In

Cancer Lett

DOI

EISSN

1872-7980

Publication Date

January 2019

Volume

440-441

Start / End Page

1 / 10

Location

Ireland

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitin-Protein Ligases
  • Signal Transduction
  • Pyridazines
  • Proto-Oncogene Proteins c-pim-1
  • Protein Kinase Inhibitors
  • Proteasome Endopeptidase Complex
  • Peptide Hydrolases
  • Oncology & Carcinogenesis
  • Multiple Myeloma