FJ: Searching for selective cyclin-dependent kinase inhibitors to target the retinoblastoma/p16 cancer gene pathway

The retinoblastoma protein (pRb)/cyclin/cyclin-dependent kinase (Cdk)/p16 tumor-suppressor pathway participates in the regulation of cellular proliferation and undergoes mutational or epigenetic inactivation in essentially 100 % of selected human malignancies, including lung cancer (1,2). Since this pathway is frequently altered by inactivation of either the RB gene or the upstream Cdk4/6-inhibitor gene, Cdkn2a/p16ink4a, it is com-monly referred to as the RB/p16 tumor-suppressor pathway. Within this tumor-suppressor pathway, the loss of p16 function results in constitutive Cdk4/6 activation that confers aberrant pRb hyperphosphorylation. pRb hyperphosphorylation, in turn, locks the protein in an “inactive ” conformation that disrupts the function of downstream cellular-binding partners, such as mem-bers of the E2F family of transcription factors. Surprisingly, the deregulation of E2F by aberrant Cdk activation appears to b