This application focuses on the cyclin-dependent kinase 5 (CDK5). The overarching goal of this proposal is to
test whether inhibition of CDK5 kinase might represent an effective therapeutic strategy in treatment of
metastatic melanomas. In our study, we will utilize human cancer cell lines as well as mouse cancer models.
Our work may lead to a novel therapeutic approach for cancer patients centered on CDK5 inhibition. Despite
its name, CDK5 is not regulated by cyclins. CDK5 is inactive in its monomeric form, and its kinase activity is
triggered by interaction with non-cyclin proteins termed p35 and p39. During normal development, CDK5-p35
and CDK5-p39 kinases are active in the nervous system. CDK5-p35/p39 kinases were shown to regulate a
wide range of neuronal functions, including terminal differentiation, synapse formation and plasticity, axon
guidance, neurite outgrowth, membrane transport and neuronal migration, through phosphorylation of various
neuronal substrates. Growing evidence indicates that CDK5 plays an important role in tumorigenesis. Several
studies documented that human cancer cells express CDK5 and p35/p39, and contain catalytically active
CDK5-p35/p39 complexes. High expression of CDK5 in tumors was shown to confer overall poor prognosis.
The exact molecular function of CDK5 in tumor cells is not fully understood. It has been postulated that CDK5
affects cell proliferation, or regulates tumor cell migration, or survival, with different studies ascribing activating
or inhibitory roles for CDK5 in these processes. In our study, we decided to focus on melanoma, as this tumor
type expressed particularly high CDK5 levels. We obtained preliminary evidence that CDK5 plays an important
role in tumor cell invasiveness and metastasis. We obtained preliminary results about the molecular role
played by CDK5 in the metastatic spread of tumor cells. We also developed a novel mouse strain that allows
us to switch off CDK5 activity in vivo. In the work proposed in this application, we will extend these findings. In
Specific Aim 1, we will utilize our strain of mice that allows an acute shutdown of CDK5, along with a well-
established mouse model of melanoma, to further study the role of CDK5 in melanoma metastasis in vivo. In
Aim 2, we will follow up on our preliminary results, and we will determine the exact molecular function played
by CDK5 in melanoma metastasis. Lastly, in a translational Aim 3, we will perform a pre-clinical study to test
whether inhibition of CDK5 kinase would block the metastatic spread of human melanomas, using a large
collection of human patient-derived xenografts (PDX). The expected overall impact of this proposal is that it
will elucidate the molecular function of CDK5 in melanoma cells, and will lead to novel targeted therapeutic
strategies centered on CDK5 inhibition.