**2. Role of cyclin-dependent kinases in carcinogenesis**

As important components of cell cycle activation and control the Cyclin-dependent kinase protein family contributes to tumor development and, in fact, an universal abnormal regulation of Cdk pathways has been described in human tumors induced by multiple mechanisms (Malumbres & Barbacid, 2009). Various genetic and epigenetic alterations in

The second group of proteins belonging to Cdk family Cdk7 to Cdk13 are involved in the activation of cell cycle kinases and transcriptional regulation (Akoulitchev et al., 2000; Chen et al., 2006; Chen et al., 2007; Garriga & Grana, 2004; Hu et al., 2007; Kasten & Giordano, 2001). Cdk7 in complex with Cyclin H is given a special importance since it is the only Cdk activating kinase (CAK) in mammalian cells phosphorylating a threonine residue

Fig. 1. Overview of human cell cycle activation and transcriptional regulation through Cdk-

As important components of cell cycle activation and control the Cyclin-dependent kinase protein family contributes to tumor development and, in fact, an universal abnormal regulation of Cdk pathways has been described in human tumors induced by multiple mechanisms (Malumbres & Barbacid, 2009). Various genetic and epigenetic alterations in

**2. Role of cyclin-dependent kinases in carcinogenesis** 

Cyclin complexes

in the conserved T-loop of Cdk (Lolli & Johnson, 2005).

human cancer including mutations and amplification of Cdk and positive regulatory Cyclin subunits, mutations or silencing of substrates (Rb) and endogenous Cdk inhibitors (INK4, Cip/ Kip proteins) lead to a hyperactivation of Cdk regulatory pathways (Table 1) (Deshpande et al., 2005; Malumbres & Barbacid, 2005). In consequence, critical cell cycle checkpoints are ignored resulting in abnormal cell proliferation and tumor progression.

Although tumor cells exhibit rather infrequent mutations of *cdk* genes with the exception of G1 kinases Cdk4 and Cdk6 amplification, overexpression or hyperactivation of basic cell cycle regulators is a general feature of human tumors (Easton et al., 1998; Kim et al., 1999; Sotillo et al., 2001; Wolfel et al., 1995). Cdk hyperactivation is often affected by mutations of Cdk regulatory subunits. In consequence, overexpression of Cyclin A, Cyclin B, Cyclin E, and Cyclin D were reported in a wide spectrum of tumors, like leukemia or carcinomas and were associated with poor prognosis (Johansson & Persson, 2008; Ko et al., 2009). A common alteration in human tumors was demonstrated for tumor suppressor gene *rb*. Altered Rb proteins, momentous for transcriptional control, are insensitive to Cdk regulation and accelerate cell cycle progression (Nevins, 2001). Finally, abnormal regulation or inactivation of Cdk endogenous inhibitors p15*INK4B*, p16*INK4A* and p27*Kip1* was described in numerous human tumors leading to enhanced Cdk activity (Ruas & Peters, 1998; Tsihlias et al., 1999).


Table 1. Genetic and epigenetic alterations of Cdk pathway components in human cancer (Graf et al., 2010; Ortega et al., 2002; Weinberg, 2007)

Cyclin-Dependent Kinases (Cdk) as Targets for Cancer Therapy and Imaging 269

Fig. 2. Molecular structures of selected Cdk inhibitors tested in clinical trials at the time

Most of the Cdk inhibitors are less selective and affect several Cdk family members, not only resulting in cell cycle arrest via blocking of Cdk1, Cdk2, and Cdk4, but also in manipulation of RNA synthesis through targeting of transcriptional kinases Cdk7 and Cdk9. Combination of cell cycle kinase inactivation and Cdk9 inhibition has been shown to trigger cell death via promotion of apoptosis in tumor cells (Cai et al., 2006). Otherwise, toxic effects of transcriptional manipulation in non-tumor cells via inhibition of Cdk7 and Cdk9 could be crucial for therapeutic application of single agent Cdk inhibitors. In addition, it has to be considered, that unselective targeting of transcriptional Cdk, e. g., Cdk10 and Cdk11 would

*pan-Cdk inhibitors* 

Universal abnormal regulation of Cdk pathways especially in G1/ S phase suggests involvement and importance of these kinases in carcinogenesis, despite of uncertain results concerning dependence of Cdk2, Cdk4 and Cdk6 on cell cycle progression in embryogenesis (Malumbres & Barbacid, 2009; Santamaria et al., 2007).

In consequence, cell cycle regulating Cdks are attractive molecular targets for new (radio)pharmaceutical strategies in both cancer therapy and diagnosis, considering the heterogeneity of Cdk activity in different human tumor types. Compounds directly inhibiting the cell cycle machinery hold promise in restoring missing cellular Cdk regulators and arrest of proliferating cells, thus providing a non-genotoxic therapy modality. Conspicuous amplification of Cdk in tumor cells provides an opportunity for visualization of tumors by means of positron emission tomography (PET).
