Figure 1. Transcriptional responses to CDK4/6 inhibition. The pharmaceutical inhibition of CDK4/6 results in two distinct series of transcriptional programs. First, CDK4/6 inhibition results in the blockade of RB phosphorylation and enhanced RB-mediated transcriptional repression. This gene expression program is highly conserved and involves multiple genes that are “universally” required for proliferation. These genes play critical roles in DNA replication, DNA repair, and mitotic progression. In contrast, there is poorly understood cadre of genes that are regulated as a consequence of CDK4/6 inhibition. The mechanisms and pathways that lead to the induction of these genes is poorly understood, as is their significance to the functional effects of CDK4/6 inhibition. Specifically, they could represent off-target effects from the inhibitors, additional non-canonical targets for CDK4/6, or context specific targets for the RB tumor suppressor.