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

• Published in: Cancer letters Vol. 440-441; pp. 1 - 10
• Main Authors: Zheng, Jing, Sha, Yonggang, Roof, Logan, Foreman, Oded, Lazarchick, John, Venkta, Jagadish Kummetha, Kozlowski, Cleopatra, Gasparetto, Cristina, Chao, Nelson, Ebens, Allen, Hu, Jianda, Kang, Yubin
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.01.2019; Elsevier Limited
• Subjects: Animals; Apoptosis; Bone marrow; Cancer therapies; Cell cycle; Cell growth; Cereblon; Conflicts of interest; Degradation; Down-Regulation - drug effects; Enzyme inhibitors; Humans; Ikaros Transcription Factor - metabolism; IKZF1/3; Imidazoles - pharmacology; Immunoglobulins; Immunomodulation; Inhibitors; Kinases; Lenalidomide; Lenalidomide - pharmacology; Leukemia; Mice; Mice, Inbred C57BL; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - enzymology; Multiple Myeloma - metabolism; Pan-PIM kinase inhibitor; Pathogenesis; Peptide Hydrolases - biosynthesis; Peptide Hydrolases - metabolism; Pharmaceuticals; Proteasome Endopeptidase Complex - metabolism; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-pim-1 - antagonists & inhibitors; Proto-Oncogene Proteins c-pim-1 - metabolism; Pyridazines - pharmacology; Signal Transduction - drug effects; Stem cells; Toxicity; Transcription factors; Tumor cell lines; Tumors; Ubiquitination; Xenograft Model Antitumor Assays; Xenografts; IKZF1/3; Pan-PIM kinase inhibitor; Lenalidomide; Cereblon; Multiple myeloma
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.10.003

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. •Pan-PIM kinase inhibitors (SGI1776 and CX6258) exhibited significant anti-myeloma activity.•Combining a pan-PIM kinase inhibitor with lenalidomide showed synergistic anti-myeloma effects without added toxicities.•Combining pan-PIM kinase inhibitors with lenalidomide enhanced the degradation of IKZF1 and IKZF3.•Elevated expression of cereblon by pan-PIM kinase inhibitors prompted the degradation of IKZF1 and IKZF3.