The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells

• Published in: Leukemia Vol. 26; no. 12; pp. 2554 - 2557
• Main Authors: Johnson, A J, Yeh, Y-Y, Smith, L L, Wagner, A J, Hessler, J, Gupta, S, Flynn, J, Jones, J, Zhang, X, Bannerji, R, Grever, M R, Byrd, J C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2012; Nature Publishing Group
• Subjects: 631/67/327; 631/80/82/23; 692/699/67/1059/99; 692/699/67/1990/283/1895; Apoptosis; Biological and medical sciences; Bone marrow; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cancer Research; Care and treatment; Chronic lymphocytic leukemia; Critical Care Medicine; Cyclin-dependent kinase; Cyclin-dependent kinases; Cyclin-Dependent Kinases - antagonists & inhibitors; Cytokines; Cytokines - metabolism; Enzyme inhibitors; Flow Cytometry; Health aspects; Hematologic and hematopoietic diseases; Hematology; Humans; Induction therapy; Intensive; Internal Medicine; Kinases; letter-to-the-editor; Letters to the editor; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphatic leukemia; Lymphoma; Medical sciences; Medicine; Medicine & Public Health; Multiple myeloma; Oncology; Physiological aspects; Protein Kinase Inhibitors - pharmacology; Pyridinium Compounds - pharmacology; Stem cell transplantation; Tumor Cells, Cultured; Tumor Microenvironment - drug effects; Working groups; France; Chronic lymphocytic leukemia; Hematology; Cell death; Lymphoproliferative syndrome; Cytokine; Malignant hemopathy; Cancer; Apoptosis; Cyclin dependent kinase inhibitor
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.144

The cyclin dependent kinase (CDK) inhibitor flavopiridol has demonstrated promising clinical results in relapsed CLL patients leading to efforts to develop improved CDK inhibitors. Dinaciclib (SCH727965) is a pan-CDK inhibitor, derived from a detailed screen in ovarian xenograft mouse models for therapeutic index, whose toxicity in solid tumor phase I studies appears favorable. Dinaciclib in CLL cells demonstrates concentration dependent apoptosis that is superior to flavopiridol following a clinically relevant 2-hour exposure. Dinaciclib potently down-regulates expression of Mcl-1 in CLL cells and antagonizes protection mediated by multiple soluble proteins important in the microenvironment of CLL including TNF-α IL-4, BAFF, and CD40-ligand. In contrast, contact with stromal cells or fibronectin abrogates the cytotoxicity of dinaciclib that is antagonized by a pan inhibitor and p110 alpha isoform specific inhibitor of the phosphatidylinositol 3-kinase pathway suggesting potential for combination strategies. These data justify clinical development of dinaciclib in CLL.