Targeting cyclin dependent kinase 5 in hepatocellular carcinoma

For a long time cyclin dependent kinase 5 (Cdk5) was thought to be
of exclusive importance in neuronal cells. However, recently
increasing evidence suggests a function of Cdk5 in cancer
progression. In the present study, we examined the role of Cdk5 in
hepatocellular carcinoma (HCC), a highly chemoresistant cancer with
poor prognosis. Consequently, development of novel targeted
therapies for HCC is of paramount clinical importance. Analysis of
human HCC patient samples showed an increased expression of Cdk5 as
compared to normal liver tissues. Functional ablation of Cdk5
significantly decreases HCC cell proliferation and clonogenic
survival, and reduces cell motility and invasion. Of note, genetic
as well as pharmacologic inhibition of Cdk5 also shows in vivo
efficacy in a HCC xenograft mouse model. Investigating the
mechanism behind these functional effects revealed that Cdk5 is
most active in the nucleus of cells in G2/M phase. In this cell
cycle phase DNA damage response takes place, which is affected by
Cdk5 inhibition. Furthermore, Cdk5 leads to phosphorylation of
Ataxia Telangiectasia Mutated (ATM) and thereby influence its
downstream signaling. Importantly, combination of Cdk5 inhibition
with different DNA damage inducing chemotherapeutics or the
first-line systemic drug sorafenib inhibits synergistically HCC
tumor progression. In conclusion, we introduce: 1. Cdk5 as a novel
drugable target for treatment of HCC 2. The combination of Cdk5
inhibition and DNA damage agents as a novel therapeutic approach 3.
An increased efficacy of sorafenib treatment by combing with Cdk5
inhibition