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  • br Cyclin dependent kinases control more than cell cycle CDK


    Cyclin-dependent kinases control more than cell cycle CDKs’ roles conducting the concert of 3-Deazaadenosine was first revealed in the context of the tumor suppressor Rb, phosphorylation of which by CDK4 or CDK6 inactivates it loosing the transcription factor E2F [1], [12], [15]. Discovery of other cyclin/CDK combinations and their role in other phases of the cell cycle (Table 1), including in cancer cells, followed [16], [17], [18], [19], [20]. Apart from CDK1 (“maturation promoting factor”), the only CDK apparently absolutely required for cell cycle, knockout of other CDKs does not arrest the cell cycle in normal cells, and mice with non-CDK1 CDK knockouts can develop at least until mid-gestation [21]. This redundancy of CDK1 with respect to cell cycle provides at least some clue that other CDKs may have other functions. In a turn of events that has become common as we understand more about the diverse functions of genes and proteins, CDKs were subsequently found to have additional and diverse functions beyond those for which they were named (viz, cell cycle). For example, CDK1 may directly phosphorylate Bcl-2 family proteins [22], while CDK4 is involved in glucose metabolism independent of its role in E2F mediated cell-cycle progression [23]. CDK5 is involved in tau phosphorylation in neurons [24]. CDK4 and CDK6 have redundant roles in the cell cycle, both complexing with cyclin D, but CDK6 has recently been shown to activate hematopoietic and leukemia stem cells through regulation of Egr1 [25]. Interestingly, and particularly relevant to chronic lymphocytic leukemia as we will see later, CDK7 and CDK9 are critical cofactors in RNA transcription: CDK7 phosphorylates serines present at the C-terminal end of RNA polymerase II (PolII) allowing initiation of RNA transcription by PolII, while CDK9 also phosphorylates a serine in PolII, facilitating RNA transcript elongation [26], [27], [28].
    Cyclin-dependent kinase inhibitors An array of CDK inhibitors have been studied in the preclinical and clinical settings. Alvocidib, one the 3-Deazaadenosine first CDK inhibitors to move into clinical development has been extensively studied in chronic lymphocytic leukemia (CLL), and experience gained during its study provides a template by which to study additional agents. Subsequent agents, including dinaciclib and TG02, have been developed to have enhanced pharmacokinetic (PK) and/or pharmacodynamic properties, and both of these agents have also been studied in CLL. CDK inhibitors that have been studied in CLL are listed with their targets in Table 2. In this article, we examine the past, present, and future of CDK inhibitor development in CLL, focusing on the three agents with which there is the most clinical experience: alvocidib (flavopiridol), dinaciclib, and TG02.
    Other CDK inhibitors A multitude of other CDK inhibitors have been synthesized and some have been tried in CLL. Presently, the CDK inhibitor showing the most promise in cancer at large is palbociclib. Palbociclib (PD-0332991, Ibrance, Pfizer, New York, NY) is the first US Food and drug Administration (FDA)-approved CDK inhibitor. It has potent selectivity for CDK4 and CDK6 and is indicated for the treatment of breast cancer where it has been studied so far in phase II; the FDA approved it under the accelerated approval pathway in February 2015 and phase III studies are now underway. Although this agent has not been examined in CLL to our knowledge, it has demonstrated both clinical responses in patients with mantle cell lymphoma (MCL) as well as demonstrated the ability to overcome ibrutinib resistance in vitro [73], [74]. Although CLL is not believed to be cyclin D–driven in the same way as MCL, there nevertheless remains a great deal of overlap in disease biology, and the potential of overcoming ibrutinib resistance is particularly relevant to CLL and should be explored further, especially in the case of Richter transformation subsequent to ibrutinib, a dire situation with no good current therapy.