Selective killing of transformed cells by cyclin/cyclin-dependent kinase 2 antagonists

Recent studies identified a short peptide motif that serves as a docking site for cyclin/cyclin-dependent kinase (CDK) 2 complexes. Peptides containing this motif block the phosphorylation of substrates by cyclin A/CDK2 or cyclin E/CDK2. Here we report that cell membrane-permeable forms of such peptides preferentially induced transformed cells to undergo Apoptosis relative to nontransformed cells. Deregulation of E2F family transcription factors is a common event during transformation and was sufficient to sensitize cells to the cyclin/CDK2 inhibitory peptides. These results suggest that deregulation of E2F and inhibition of CDK2 are synthetically lethal and provide a rationale for the development of CDK2 antagonists as antineoplastic agents.