CDK/CCN and CDKI Alterations for Cancer Prognosis and Therapeutic Predictivity

Abstract

The regulation of cell growth and division occurs in an accurate sequential manner. It is dictated by the accumulation of cyclins (CCNs) and cyclin-dependent kinases (CDKs) complexes and degradation of CCNs. In human tumors, instead, the cell cycle is deregulated, causing absence of differentiation and aberrant cell growth. Oncogenic alterations of CCNs, CDKs, and CDKIs have been reported in more than 90% of human cancers, and the most frequent are those related to the G1 phase. Several molecular mechanisms, including gene overexpression, chromosomal translocations, point mutations, insertions and deletions, missense and frame shift mutation, splicing, or methylation, may be responsible for these alterations. The cell cycle regulators are involved in tumor progression given their association with cancers characterized by higher incidence of relapses and chemotherapy resistance. In the last decade anticancer drug researches focused on new compounds, able to target molecules related to changes in genes associated with tumor status. Recently, the studies have focused on the restoration of cell cycle control modulating molecular targets involved in cancer-cell alterations. This paper aims to correlate alterations of cell cycle regulators with human cancers and therapeutic responsivity.

The tumor-associated YB-1 protein: new player in the circadian control of cell proliferation

“…Indeed mutations in cell cycle genes have been encountered in 90% of human cancers [43]. However, disruption of normal circadian clock function has also been linked with tumorigenesis [44].…”

The dynamic control of signal transduction networks in cancer cells

“…Drugs inhibiting CDKs show encouraging results in clinical trials 16 . Cell cycle aberrations are com mon in cancer 17 , and knocking out CDKs or cyclins in mice is, unexpectedly, not deleterious 18 . These observations endorse CDKs as promising targets for cancer treatment.…”

Pharmacokinetics and biodistribution of recently-developed siRNA nanomedicines

“…CDKs are also serine/threonine kinases and essential for the regulation of the cell cycle progression [48]. The abnormal expression or activity of distinct CDK complexes causes cells escape from a well-controlled cell cycle, resulting in malignant transformation [49–51]. Palbociclib, an inhibitor of CDK4/6, received Breakthrough Therapy designation from the FDA in April 2013, for the initial treatment of patients with breast cancer [52].…”