Figure 1.

Targeting dysregulation of Cyclin D–CDK4/6 axis by CDK4/6 inhibition. Cyclin D-CDK4/6-mediated RB phosphorylation occurs upon activation of Cyclin D-CDK4/6 complex in response to extracellular signals such as stimulatory mitogens, leading to ensuing cell cycle progression. Initially, upon Cyclin D-CDK4/6-mediated RB phosphorylation, RB affinity to E2F is reduced, promoting transcription of genes such as Cyclin E2. Subsequently, the Cyclin E2-CDK2 complex hyperphosphorylates RB, which induces full dissociation of the RB-E2F complex and transcription of genes encoding proteins playing critical roles in the next phases of the cell cycle. The p16^INK4A (p16) tumor suppressor encoded by CDKN2A directly binds to CDK4/6 and inhibits the formation of the Cyclin D-CDK4/6 complex and prevents Cyclin D-CDK4/6-mediated RB phosphorylation. A dysregulated Cyclin D–CDK4/6 axis, which leads to uncontrolled cell proliferation, can be inhibited by CDK4/6 inhibitors. Chronic inhibition of CDK4/6 can trigger the upregulation of PI3K and MAPK pathways to compensate for inhibitory effects of CDK4/6 inhibitors on cell cycle progression by activation of D type cyclins. Dual inhibition of CDK4/6 and PI3K/mTOR or MEK may be an efficient combination treatment to prevent the compensatory effect of the PI3K or MAPK pathways on the development of CDK4/6 inhibitor resistance.