Figure 2. Deepening cell cycle exit with combination therapies:

While the RB1-pathway is generally considered linear, the activity of both CDK4/6 and CDK2 can be induced by oncogenic signaling pathways. In the context of CDK4/6 inhibition, there can be adaptive upregulation of both cyclin D1 and cyclin E. These processes are linked to oncogenic signaling and can be ameliorated by productive combination therapies with agents targeting different signaling pathways. The basis for this cooperation is believed to involve the inhibition of CDK2 activity and maintenance of RB1 activity.