Transformed cells are sensitized to a cdk2 inhibitor during S phase. During normal cell cycle progression (top), cyclin A–cdk2 phosphorylates E2F-bound DP-1 in order to downregulate E2F at the appropriate time and allow orderly S phase progression. Following recruitment to S phase by chemotherapy agents (bottom), inhibition of cyclin A–cdk2 prevents E2F-1/DP-1 phosphorylation, resulting in inappropriately persistent E2F-1 activity and eventual apoptosis.