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Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia
Author(s) -
Chen Yixiang,
Germano Sandra,
Clements Chris,
Samuel Jesvin,
Shelmani Ghalia,
Jayne Sandrine,
Dyer Martin J. S.,
Macip Salvador
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14285
Subject(s) - cancer research , ibrutinib , cyclin dependent kinase , chronic lymphocytic leukemia , protein kinase b , mcl1 , cdk inhibitor , pi3k/akt/mtor pathway , apoptosis , biology , signal transduction , medicine , immunology , cell cycle , leukemia , microbiology and biotechnology , downregulation and upregulation , biochemistry , gene
Summary Dinaciclib is a cyclin‐dependent kinase inhibitor with clinical potential in different cancers, including chronic lymphocytic leukaemia ( CLL ). In order to better understand its cytotoxic action, we characterized its effects on signalling pathways important for the survival of CLL cells. We found that dinaciclib induced apoptosis through the activation of caspases 8 and 9, which was independent of the presence of cytokines to mimic the environment of proliferation centres or IGVH mutation status. Moreover, treatment with dinaciclib led to the inhibition of oncogenic pathways normally activated in stimulated CLL cells, such as STAT 3, NF ‐κB, p38, PI 3K/ AKT and RAF / MEK / ERK . Dinaciclib was also able to block the expression of anti‐apoptotic proteins of the BCL 2 family such as MCL 1 and BCL ‐ xL (also termed BCL 2L1). Finally, we showed that low concentrations of dinaciclib enhanced cell sensitivity to ibrutinib and the BCL 2 inhibitor ABT ‐199, two drugs with known effects on CLL . Taken together, our data show that dinaciclib targets multiple pro‐survival signalling pathways in CLL , which provides a mechanistic explanation for its potent induction of apoptosis. They also support a therapeutic application of cyclin‐dependent kinase inhibitors in CLL in combination with other relevant targeted therapies.