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

Recent studies identified a short peptide motif that serves as a docking si te for cyclin/cyclin-dependent kinase (cdk) 2 complexes. Peptides containin g this motif block the phosphorylation of substrates by cyclin A/cdk2 or cy clin E/cdk2. Here we report that cell membrane-permeable forms of such pept ides 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 cel ls to the cyclin/cdk2 inhibitory peptides, These results suggest that dereg ulation of E2F and inhibition of cdk2 are synthetically lethal and provide a rationale for the development of cdk2 antagonists as antineoplastic agent s.